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  • 更新日期:2018-07-16
  • Blueprints for the Rational Design of Therapeutic Mutacin 1140 Variants
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2018-07-16
    Johan A. Kers; R. Eryl Sharp; Sheela Muley; Melissa Mayo; Jeffrey Colbeck; Yihui Zhu; Anthony W. DeFusco; Jae H. Park; Martin Handfield
  • Theranostics and Image Guided Drug Delivery. Edited by Maya Thanou
    ChemMedChem (IF 3.009) Pub Date : 2018-07-16
    Eva Toth; Sara Lacerda
  • Tertiary‐Amine‐Based Inhibitors of the Astacin Protease Meprin α
    ChemMedChem (IF 3.009) Pub Date : 2018-06-21
    Kathrin Tan; Christian Jäger; Dagmar Schlenzig; Stephan Schilling; Mirko Buchholz; Daniel Ramsbeck
  • Design and synthesis of DNA‐interactive β‐carboline‐oxindole hybrids as cytotoxic and apoptosis inducing agents
    ChemMedChem (IF 3.009) Pub Date : 2018-07-16
    Shankaraiah Nagula; Ramya Tokala; Sowjanya Thatikonda; Sravani Sana; Usha Sree Vanteddu; Chandraiah Godugu

    A new series of (E)‐3‐((1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene)indolin‐2‐one hybrids have been synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines namely, HCT‐15, HCT‐116, A549, NCI‐H460, MCF‐7 including HFL. Among the tested compounds, 10s showed potent cytotoxicity against HCT‐15 cancer cells with an IC50 value of 1.43 ± 0.26 μM and GI50 value of 0.89 ± 0.06 μM. Notably, induction of apoptosis by 10s on HCT‐15 cell line was characterized by using different staining techniques such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10s arrests the HCT‐15 cancer cells at the G0/G1 phase of cell cycle. Additionally, western blot analysis indicated, the treatment of 10s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, 8, 9 and cleaved PARP with reference to actin. Next, clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10s, in a dose‐dependent manner. Moreover, the compounds when tested on normal human lung cells (HFL) were observed to be safer with low toxicity profile. In addition, viscosity and molecular docking studies showed that compound 10s having typical intercalation with DNA.

  • Progress in the Development of Platelet‐Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases
    ChemMedChem (IF 3.009) Pub Date : 2018-07-15
    Isabel Hyland; Ronan O'Toole; Jason Smith; Alex C. Bissember

    Platelet‐Activating Factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr receptor remains unknown, the PAFr is a well‐established therapeutic target and an array of structurally diverse PAFr antagonists have been identified. This ranges from compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes. This review updates over 20 years of progress in this area. The development and synthesis of new PAFr antagonists, structure‐activity relationship studies, the biological activity of these molecules, and their therapeutic potential are discussed.

  • Nucleoside triphosphate cosubstrates control the substrate profile and efficiency of aminoglycoside 3′-O-phosphotransferase type IIa
    Med. Chem. Commun. (IF 2.342) Pub Date : 2018-07-16
    Selina Y. L. Holbrook, Matthew S. Gentry, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
  • Synthesis and Evaluation of a Novel Bivalent Selective Antagonist for the Mu-Delta Opioid Receptor Heterodimer that Reduces Morphine Withdrawal in Mice
    J. Med. Chem. (IF 6.253) Pub Date : 2018-07-16
    Keith M. Olson, Attila Keresztes, Jenna K. Tashiro, Lisa V. Daconta, Victor J. Hruby, John M. Streicher
  • Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses
    J. Med. Chem. (IF 6.253) Pub Date : 2018-07-16
    Vrajesh Bhaskarbhai Pandya, Sanjay Kumar, Sachchidanand Sachchidanand, Rajiv Sharma, Ranjit C Desai

    The nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORγ or RORc) is a key transcription factor for the production of pro-inflammatory cytokines implicated in the pathogenesis of autoimmune diseases. Recently, small molecule inhibitors of RORc drew the enormous attention of the research community worldwide, as a possible therapy for autoimmune diseases, mediated by the IL-17 cytokine. With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases.

  • Challenges in Transitioning Cocrystals from Bench to Bedside: Dissociation in Prototype Drug Product Environment
    Mol. Pharmaceutics (IF 4.556) Pub Date : 2018-07-16
    Sampada Koranne, Anasuya Sahoo, Joseph F. Krzyzaniak, Suman Luthra, Kapildev K. Arora, Raj Suryanarayanan
  • 更新日期:2018-07-16
  • 更新日期:2018-07-15
  • A Novel Pyrrole-Imidazole Polyamides Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth
    J. Med. Chem. (IF 6.253) Pub Date : 2018-07-14
    Zhehong Cheng, Wei Wang, Chunlei Wu, Xiaohua Zou, Lijing Fang, Wu Su, Pu Wang

    Epstein-Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV positive tumor cells. EBNA1 binds to the origin of virus plasmid replication (OriP) on EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst 33258 conjugate named EIP-2 (2), which selectively binds to the OriP region with high affinity, to interrupt EBNA1-OriP binding in vitro and in vivo. By eradicating EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV-positive cell proliferation. Moreover, injection of 2 significantly suppressed tumor growth in mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors.

  • ROCK inhibition in models of neurodegeneration and its potential for clinical translation
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-03
    Jan Christoph Koch, Lars Tatenhorst, Anna-Elisa Roser, Kim-Ann Saal, Lars Tönges, Paul Lingor

    Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches.In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed.Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.

  • Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-03
    Yanxin Lu, Yang Liu, Ying Pang, Karel Pacak, Chunzhang Yang

    DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA repair pathways predict therapy resistance and disease outcome. Members of the poly (ADP-ribose) polymerase (PARP) family initiate and organize the biologic process of DNA repair, which counteracts many types of chemotherapies. Since the first development in approximately 3 decades ago, PARP inhibitors have greatly changed the concept of cancer therapy, leading to encouraging improvements in tumor suppression and disease outcomes. Here we summaries both pre-clinical and clinical findings of PARP inhibitors applications, particularly for combination therapies.

  • Cancer development and therapy resistance: spotlights on the dark side of the genome
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-10
    Eleonora Leucci

    Cancer research has been focusing so far on genetic alterations in protein-coding genes. However, mounting evidence underlines the importance of epigenetic and post-transcriptional events in cancer progression and therapy resistance. Moreover, recent genome-wide studies show that disease-causing mutations and chromosome rearrangements often span areas of the genome that do not contain any known protein-coding gene. This finding is not surprising, considering that even though the vast majority of the human genome is transcribed, only a minor portion (accounting for less than 2%) encodes for proteins. Among the various classes of transcribed RNAs, long non-coding RNAs are attractive biomarkers and therapeutic targets due to their disease- and stage-restricted expression.In addition, by taking part in all the major epigenetic and post-transcriptional programs in the cell, long non-coding RNAs are emerging as key regulators of stress responses and therefore they are important non-genetic players in cancer development and progression. Here I discuss the role of lncRNAs in cancer and their promises and pitfalls as biomarkers and therapeutic targets.

  • Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-13
    Jonas R.M. Van Audenaerde, Geert Roeyen, Phillip K. Darcy, Michael H. Kershaw, M. Peeters, Evelien L.J. Smits

    Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.

  • Tools and drugs for uracil nucleotide-activated P2Y receptors
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-13
    Muhammad Rafehi, Christa E. Müller

    P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y2 (UTP, also ATP and dinucleotides), P2Y4 (UTP), P2Y6 (UDP), and P2Y14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y2R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y2R antagonist is AR-C118925 (10-01). For studies of the P2Y4R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y6R agonists have been developed including 5-methoxyuridine 5′-O-((Rp)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y6R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y14R agonist is available, while PPTN (10-14) represents a potent and selective P2Y14R antagonist. The radioligand [3H]UDP can be used to label P2Y14Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.

  • DNA mismatch repair in cancer
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-15
    Marina Baretti, Dung T. Le

    Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers. Here we will discuss the current methods to detect MSI/MMR deficiency with a focus of new tools which are emerging as highly sensitive detector for MSI across multiple tumor types.Due to high frequencies of non-synonymous mutations, the presence of frameshift-mutated neoantigens, which can trigger a more robust and long-lasting immune response and strong TIL infiltration with tumor eradication, MSI has emerged as an important predictor of sensitivity for immunotherapy-based strategies, as showed by the recent FDA's first histology agnostic-accelerated approval to immune checkpoint inhibitors for refractory, adult and pediatric, MMR deficient (dMMR) or MSI high (MSI-H) tumors. Moreover, it is known that MSI status may predict cancer response/resistance to certain chemotherapies.Here we will describe the complex interplay between the genetic and clinical-pathological features of MSI/dMMR tumors and the cancer immunotherapy, with a focus on the predictive and prognostic role of MMR status for immune checkpoint inhibitors (ICIs) and providing some suggestions on how to conceive better predictive markers for immunotherapy in the next future.

  • Vitamin C for the treatment of sepsis: The scientific rationale
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-21
    Paul E. Marik

    Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.

  • The G protein-coupled receptor GPR34 – The past 20 years of a grownup
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22
    Torsten Schöneberg, Jaroslawna Meister, Alexander Bernd Knierim, Angela Schulz

    Research on GPR34, which was discovered in 1999 as an orphan G protein-coupled receptor of the rhodopsin-like class, disclosed its physiologic relevance only piece by piece. Being present in all recent vertebrate genomes analyzed so far it seems to improve the fitness of species although it is not essential for life and reproduction as GPR34-deficient mice demonstrate. However, closer inspection of macrophages and microglia, where it is mainly expressed, revealed its relevance in immune cell function. Recent data clearly demonstrate that GPR34 function is required to arrest microglia in the M0 homeostatic non-phagocytic phenotype. Herein, we summarize the current knowledge on its evolution, genomic and structural organization, physiology, pharmacology and relevance in human diseases including neurodegenerative diseases and cancer, which accumulated over the last 20 years.

  • Imaging techniques to study drug transporter function in vivo
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22
    Nicolas Tournier, Bruno Stieger, Oliver Langer

    Transporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.

  • Bile acid regulation: A novel therapeutic strategy in non-alcoholic fatty liver disease
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-22
    Qinwei Yu, Zhenzhou Jiang, Luyong Zhang

    Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat deposition in the liver in the absence of significant alcohol consumption. Dysregulated bile acid (BA) metabolism is an important indicator in the pathology of NAFLD, which could progress into more severe forms of liver injury. Lipid metabolism, immune environment and intestinal bacteria are all affected by dysregulated BA metabolism directly, but the mechanisms remain unclear. Several drug candidates that target BA metabolism, either used alone or in combination with other agents, are currently under development for treatment of NAFLD. Here, we summarize the relationship of dysregulated BA metabolism and NAFLD, discuss the effects and mechanisms of dysregulated BAs-induced lipid metabolism disorder. Challenges in developing novel treatments are also discussed.

  • Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-24
    Joachim Alexandre, Javid J. Molsehi, Kevin R. Bersell, Christian Funck-Brentano, Dan M. Roden, Joe-Elie Salem

    Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or as a result of anticancer therapy. Much attention has focused on heart failure; however, other cardiotoxicities, notably cardiac rhythm disorders, can occur without underlying cardiomyopathy.Supraventricular tachycardias occur in cancer patients treated with cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs) such as ibrutinib. Ventricular arrhythmias, with a subset of them being torsades-de-pointes (TdP) favored by QTc prolongation have been reported: this may be the result of direct hERG-channel inhibition or a more recently-described mechanism of phosphoinositide-3-kinase inhibition. The major anticancer drugs responsible for QTc prolongation in this context are KIs, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, and selective estrogen receptor modulators.Anticancer drug-induced cardiac rhythm disorders remain an underappreciated complication even by experienced clinicians. Moreover, the causal relationship of a particular anticancer drug with cardiac arrhythmia occurrence remains challenging due in part to patient comorbidities and complex treatment regimens. For example, any cancer patient may also be diagnosed with common diseases such as hypertension, diabetes or heart failure which increase an individual's arrhythmia susceptibility. Further, anticancer drugs are generally usually used in combination, increasing the challenge around establishing causation.Thus, arrhythmias appear to be an underappreciated adverse effect of anticancer agents and the incidence, significance and underlying mechanisms are now being investigated.

  • Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder
    Pharmacol. Therapeut. (IF 10.376) Pub Date : 2018-04-27
    Shizuo Yamada, Yoshihiko Ito, Saori Nishijima, Katsumi Kadekawa, Kimio Sugaya

    Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non-neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose-dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications.

  • Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARα selective agonists: New leads for oculovascular conditions
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-05
    Xiao-Zheng Dou, Dinesh Nath, Younghwa Shin, Jian-Xing Ma, Adam S. Duerfeldt

    Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure–activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand–protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARα agonism. Two key observations arose from this work 1) contrary to other PPARα agonists, incorporation of the fibrate “head-group” decreases PPARα selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARα that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARα agonism (EC50 = ∼6 µM) than Y-0452 (EC50 = ∼50 µM) and manifests >20-fold selectivity for PPARα over the PPARγ and PPARδ isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARα agonism including PPARα upregulation, induction of target genes, and inhibition of cell migration.

  • Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-07
    Munia F. Sowaileh, Amy E. Salyer, Kuldeep K. Roy, Jinu P. John, James R. Woods, Robert J. Doerksen, Gregory H. Hockerman, David A. Colby

    β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.

  • Covalent inhibitors of nicotinamide N-methyltransferase (NNMT) provide evidence for target engagement challenges in situ
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-10
    Hsin-Yu Lee, Radu M. Suciu, Benjamin D. Horning, Ekaterina V. Vinogradova, Olesya A. Ulanovskaya, Benjamin F. Cravatt

    Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide using S-adenosyl-L-methionine (SAM) as a methyl donor and, through doing so, can modulate cellular methylation potential to impact diverse epigenetic processes. NNMT has been implicated in a range of diseases, including cancer and metabolic disorders. Potent, selective, and cell-active inhibitors would constitute valuable probes to study the biological functions and therapeutic potential of NNMT. We previously reported the discovery of electrophilic small molecules that inhibit NNMT by reacting with an active-site cysteine residue in the SAM-binding pocket. Here, we have used activity-based protein profiling (ABPP)-guided medicinal chemistry to optimize the potency and selectivity of NNMT inhibitors, culminating in the discovery of multiple alpha-chloroacetamide (αCA) compounds with sub-µM IC50 values in vitro and excellent proteomic selectivity in cell lysates. However, these compounds showed much weaker inhibition of NNMT in cells, a feature that was not shared by off-targets of the αCAs. Our results show the potential for developing potent and selective covalent inhibitors of NNMT, but also highlight challenges that may be faced in targeting this enzyme in cellular systems.

  • Synthesis, structure and bioactivity of primary sulfamate-containing natural products
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-16
    Prashant Mujumdar, Silvia Bua, Claudiu T. Supuran, Thomas S. Peat, Sally-Ann Poulsen

    Here we report the synthesis of natural products (NPs) 5′-O-sulfamoyl adenosine 1 and 5′-O-sulfamoyl-2-chloroadenosine 2. As primary sulfamates these compounds represent an uncommon class of NPs, furthermore there are few NPs known that contain a NS bond. Compounds 1 and 2 were evaluated for inhibition of carbonic anhydrases (CA), a metalloenzyme family where the primary sulfamate is known to coordinate to the active site zinc and form key hydrogen bonds with adjacent CA active site residues. Both NPs were good to moderate CA inhibitors, with compound 2 a 20–50-fold stronger CA inhibitor (Ki values 65–234 nM) than compound 1. The protein X-ray crystal structures of 1 and 2 in complex with CA II show that it is not the halogen-hydrophobic interactions that give compound 2 a greater binding energy but a slight movement in orientation of the ribose ring that allows better hydrogen bonds to CA residues. Compounds 1 and 2 were further investigated for antimicrobial activity against a panel of microbes relevant to human health, including Gram-negative bacteria (4 strains), Gram-positive bacteria (1 strain) and yeast (2 strains). Antimicrobial activity and selectivity was observed. The minimum inhibitory concentration (MIC) of NP 1 was 10 µM against Gram-positive Staphylococcus aureus and NP 2 was 5 µM against Gram-negative Escherichia coli. This is the first time that NP primary sulfamates have been assessed for inhibition and binding to CAs, with systematic antimicrobial activity studies also reported.

  • Inducing protein-protein interactions with molecular glues
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-19
    Ye Che, Adam M. Gilbert, Veerabahu Shanmugasundaram, Mark C. Noe

    The drugable proteome is limited by the number of functional binding sites that can bind small molecules and respond with a therapeutic effect. Orthosteric and allosteric modulators of enzyme function or receptor signaling are well-established mechanisms of drug action. Drugs that perturb protein-protein interactions have only recently been launched. This approach is more difficult due to the extensive contact surfaces that must be perturbed antagonistically. Compounds that promote novel protein-protein interactions promise to dramatically expand opportunities for therapeutic intervention. This approach is precedented with natural products (rapamycin, FK506, sanglifehrin A), synthetic small molecules (thalidomide and IMiD derivatives) and indisulam analogues.

  • Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-27
    Justin Anglin, Reza Beheshti Zavareh, Philipp N. Sander, Daniel Haldar, Edouard Mullarky, Lewis C. Cantley, Alec C. Kimmelman, Costas A. Lyssiotis, Luke L. Lairson

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of ∼800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors.

  • Activities of recombinant human bleomycin hydrolase on bleomycins and engineered analogues revealing new opportunities to overcome bleomycin-induced pulmonary toxicity
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-04-30
    Ivana Crnovcic, Fei Gan, Dong Yang, Liao-Bin Dong, Peter G. Schultz, Ben Shen

    The bleomycins (BLMs) are widely used in combination therapies for the treatment of various cancers. Dose-dependent and cumulative pulmonary toxicity is the major cause of BLM-associated morbidity, limiting the broad uses of BLMs as anticancer drugs. The organ specificity of BLM-induced toxicity has been correlated with the expression of the hBLMH gene, encoding the human bleomycin hydrolase (hBLMH), which is poorly expressed in the lung. hBLMH hydrolyzes BLMs into the biologically inactive deamido BLMs, thereby protecting organs from BLM-induced toxicity. Here we report (i) expression of hBLMH and production and isolation of recombinant human bleomycin hydrolase (rhBLMH) from E. coli, (ii) structural characterization of deamido BLM A2 and B2 isolated from rhBLMH-catalyzed hydrolysis of BLM A2 and B2, and (iii) kinetic characterization of the rhBLMH-catalyzed hydrolysis of BLM A2 and B2, in comparison with five BLM analogues. rhBLMH from E. coli catalyzes rapid and efficient hydrolysis of all BLMs tested, exhibiting a superior catalytic efficiency for BLM B2. These findings reveal new opportunities to overcome BLM-induced pulmonary toxicity in chemotherapies, potentially by exploring BLM B2 as the preferred congener, engineering designer BLMs with optimized activity for rhBLMH, or co-administrating rhBLMH directly into the lung as a potential protein therapeutic.

  • Design, solid-phase synthesis and evaluation of enterobactin analogs for iron delivery into the human pathogen Campylobacter jejuni
    Bioorg. Med. Chem. (IF 2.881) Pub Date : 2018-04-16
    Cristina Y. Zamora, Amaël G.E. Madec, Wilma Neumann, Elizabeth M. Nolan, Barbara Imperiali

    The human enteropathogen Campylobacter jejuni, like many bacteria, employs siderophores such as enterobactin for cellular uptake of ferric iron. This transport process has been shown to be essential for virulence and presents an attractive opportunity for further study of the permissiveness of this pathway to small-molecule intervention and as inspiration for the development of synthetic carriers that may effectively transport cargo into Gram-negative bacteria. In this work, we have developed a facile and robust microscale assay to measure growth recovery of C. jejuni NCTC 11168 in liquid culture as a result of ferric iron uptake. In parallel, we have established the solid-phase synthesis of catecholamide compounds modeled on enterobactin fragments. Applying these methodological developments, we show that small synthetic iron chelators of minimal dimensions provide ferric iron to C. jejuni with equal or greater efficiency than enterobactin.

  • Synthesis of (E)-cinnamyl ester derivatives via a greener Steglich esterification
    Bioorg. Med. Chem. (IF 2.881) Pub Date : 2018-04-20
    Andrew B. Lutjen, Mackenzie A. Quirk, Allycia M. Barbera, Erin M. Kolonko

    Cinnamic acid derivatives are known antifungal, antimicrobial, antioxidant, and anticancer compounds. We have developed a facile and mild methodology for the synthesis of (E)-cinnamate derivatives using a modified Steglich esterification of (E)-cinnamic acid. Using acetonitrile as the solvent, rather than the typical chlorinated solvent, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the coupling agent enables ester conversion in 45 min with mild heating (40–45 °C) and an average yield of 70% without need for further purification. These conditions were used to couple (E)-cinnamic acid with 1° and 2° aliphatic alcohols, benzylic and allylic alcohols, and phenols. This work demonstrates a facile and greener methodology for Steglich esterification reactions.

  • Screening serine/threonine and tyrosine kinase inhibitors for histidine kinase inhibition
    Bioorg. Med. Chem. (IF 2.881) Pub Date : 2018-04-22
    Kaelyn E. Wilke, Conrad A. Fihn, Erin E. Carlson

    Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.

  • Synthesis of the ABC framework of tamulamides A and B
    Bioorg. Med. Chem. (IF 2.881) Pub Date : 2018-04-22
    Elizabeth H. Kelley, Timothy F. Jamison

    Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.

  • 更新日期:2018-07-14
  • 更新日期:2018-07-14
  • Identification and characterization of novel host defense peptides from the skin secretion of the fungoid frog, Hydrophylax bahuvistara (Anura: Ranidae)
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 11 Februar
    Thundi Parambil Vasanth Kumar Vineeth Kumar; Radhamony Asha; Gopal Shyla; Sanil George
  • An efficient and facile Green synthesis of Bisindole Methanes as potential Mtb FtsZ inhibitors
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2018-07-13
    K. Pratima; N. Goud; Arifuddin Mohammed; Gayathri Ramamoorthy; Ragamanvitha Ananthathatmula; Mukesh Doble; Arshad Rizvi; Sharmista Banerjee; Ravi Alvala; Mallika Alvala
  • Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA‐approved inhibitors: MD study
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2018-07-13
    Siyabonga I. Maphumulo; Amit K. Halder; Thavendran Govender; Sibusiso Maseko; Glenn E. M. Maguire; Bahareh Honarparvar; Hendrik G. Kruger
  • The Protein Tyrosine Phosphatase Activity of Eyes Absent Contributes to Tumor Angiogenesis and Tumor Growth
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Yuhua Wang, Ram Naresh Pandey, Stephen Riffle, Hemabindu Chintala, Kathryn A. Wikenheiser-Brokamp, Rashmi S. Hegde

    DNA damage repair capacity is required for cells to survive catastrophic DNA damage and proliferate under conditions of intratumoral stress. The ability of the minor histone protein H2AX to serve as a hub for the assembly of a productive DNA damage repair complex is a necessary step in preventing DNA damage–induced cell death. The Eyes Absent (EYA) proteins dephosphorylate the terminal tyrosine residue of H2AX, thus permitting assembly of a productive DNA repair complex. Here, we use genetic and chemical biology approaches to separately query the roles of host vascular endothelial cell and tumor cell EYA in tumor growth. Deletion of Eya3 in host endothelial cells significantly reduced tumor angiogenesis and limited tumor growth in xenografts. Deletion of Eya3 in tumor cells reduced tumor cell proliferation and tumor growth without affecting tumor angiogenesis. A chemical inhibitor of the EYA tyrosine phosphatase activity inhibited both tumor angiogenesis and tumor growth. Simultaneously targeting the tumor vasculature and tumor cells is an attractive therapeutic strategy because it could counter the development of the more aggressive phenotype known to emerge from conventional antiangiogenic agents. Mol Cancer Ther; 17(8); 1–11. ©2018 AACR.

  • Design and fabrication of dual‐targeted delivery system based on gemcitabine conjugated human serum albumin nanoparticles
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2017-06-22
    Parisa Norouzi; Mohsen amini; Fatemeh Mottaghitalab; Farnaz Sadat Mirzazadeh Tekie; Rassoul Dinarvand; Zahra Hadavand Mirzaie; Fatemeh Atyabi
  • Novel Trifluoromethylated Enobosarm Analogues with Potent Anti-androgenic Activity in vitro and Tissue Selectivity in vivo.
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    D. Alwyn Dart, Sahar Kandil, Serena Tommasini-Ghelfi, Gilberto Serrano de Almeida, Charlotte L Bevan, Wenguo Jiang, Andrew D Westwell

    Prostate cancer often develops anti‐androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis‐trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity ‐ by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR‐Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR‐Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR‐expressing tissues e.g. testes, seminal vesicles and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen ‐ thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-PTen deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.

  • Synthesis and Biological Evaluation of Novel Substituted 4‐Anilinoquinazolines as Antitumor Agents
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2015-12-21
    Dong Cao; Xiaoyan Wang; Lei Lei; Liang Ma; Zhuang Yang; Fang Wang; Lijuan Chen
  • The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Yann Wallez, Charles R. Dunlop, Timothy Isaac Johnson, Siang-Boon Koh, Chiara Fornari, James W.T. Yates, Sandra Bernaldo de Quirós Fernández, Alan Lau, Frances M. Richards, Duncan I. Jodrell

    Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard of care but shows very limited antitumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra–S-phase DNA damage response, plays a central role in safeguarding cells from replication stress and can therefore limit the efficacy of antimetabolite drug therapies. We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra–S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo . In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell-cycle arrest, and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. Moreover, synergistic growth inhibition was identified in a panel of 5 mouse and 7 human PDAC cell lines using both Bliss Independence and Loewe models. In clonogenic assays, the combination abrogated survival at concentrations for which single agents had minor effects. In vivo , AZD6738 in combination with gemcitabine was well tolerated and induced tumor regression in a subcutaneous allograft model of a KrasG12D; Trp53R172H; Pdx-Cre (KPC) mouse cancer cell line, significantly extending survival. Remarkably, the combination also induced regression of a subgroup of KPC autochthonous tumors, which generally do not respond well to conventional chemotherapy. Altogether, our data suggest that AZD6738 in combination with gemcitabine merits evaluation in a clinical trial in patients with PDAC. Mol Cancer Ther; 17(8); 1–13. ©2018 AACR.

  • Synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal and anti‐HIV activities
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2012-06-15
    Nafees Ahmed; Keyur G. Brahmbhatt; Shabana I. Khan; Melissa Jacob; Babu L. Tekwani; Sudeep Sabde; Debashis Mitra; Inder Pal Singh; Ikhlas A. Khan; Kamlesh K. Bhutani

    Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV‐1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine‐sensitive D6 strain with IC50 1.25 and 0.88 μM and chloroquine‐resistant W2 strain with IC50 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC50 2.39 and 2.78 μM and IC90 11.27 and 12.76 μM respectively. Three analogues 12c, 14c and 14i were the most active against various pathogenic bacteria and fungi with IC50 <3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV‐1. Our study demonstrated that the tricyclic guanidine compounds provide new structral class for broad spectrum activity.

  • The XPO1 Inhibitor Selinexor Inhibits Translation and Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and In Vivo
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Amy Wahba, Barbara H. Rath, John W. O'Neill, Kevin Camphausen, Philip J. Tofilon

    Analysis of the radiation-induced translatome of glioblastoma stem-like cells (GSC) identified an interacting network in which XPO1 serves as a major hub protein. To determine whether this nuclear export protein provides a target for radiosensitization, we defined the effects of clinically relevant XPO1 inhibitor selinexor on the radiosensitivity of glioblastoma cells. As determined by clonogenic survival analysis, selinexor enhanced the radiosensitivity of GSCs but not normal fibroblast cell lines. On the basis of γH2AX foci and neutral comet analyses, selinexor inhibited the repair of radiation-induced DNA double-strand breaks in GSCs, suggesting that the selinexor-induced radiosensitization is mediated by an inhibition of DNA repair. Consistent with a role for XPO1 in the nuclear to cytoplasm export of rRNA, selinexor reduced 5S and 18S rRNA nuclear export in GSCs, which was accompanied by a decrease in gene translation efficiency, as determined from polysome profiles, as well as in protein synthesis. In contrast, rRNA nuclear export and protein synthesis were not reduced in normal cells treated with selinexor. Orthotopic xenografts initiated from a GSC line were then used to define the in vivo response to selinexor and radiation. Treatment of mice bearing orthotopic xenografts with selinexor decreased tumor translational efficiency as determined from polysome profiles. Although selinexor treatment alone had no effect on the survival of mice with brain tumors, it significantly enhanced the radiation-induced prolongation of survival. These results indicate that selinexor enhances the radiosensitivity of glioblastoma cells and suggest that this effect involves the global inhibition of gene translation. Mol Cancer Ther; 17(8); 1–10. ©2018 AACR.

  • Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase‐2 for gout treatment
    Chem. Bio. Drug Des. (IF 2.328) Pub Date : 2011-10-03
    Yadi Li; Christopher M. Frenz; Zhiwen Li; Mianhua Chen; Yurong Wang; Fengjuan Li; Cheng Luo; Jian Sun; Lars bohlin; Zhenjing Li; Hua Yang; Changlu Wang

    Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX‐2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX‐2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX‐2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX‐2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX‐2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX‐2 were discussed, which is expected for further rational drug design.

  • TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Shinichi Hasako, Miki Terasaka, Naomi Abe, Takao Uno, Hirokazu Ohsawa, Akihiro Hashimoto, Ryoto Fujita, Kenji Tanaka, Takashige Okayama, Renu Wadhwa, Kazutaka Miyadera, Yoshimi Aoyagi, Kazuhiko Yonekura, Kenichi Matsuo

    Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of non–small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(8); 1–11. ©2018 AACR.

  • A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Monique J. Kauke, Alison W. Tisdale, Ryan L. Kelly, Christian J. Braun, Michael T. Hemann, K. Dane Wittrup

    Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines. Through lentiviral transduction, we generated cell lines that constitutively or through induction with doxycycline express R11.1.6 or a control protein YW1 and show specific binding by R11.1.6 to endogenous Ras through microscopy and co-immunoprecipitation experiments. Genetically encoded intracellular expression of this high-affinity Ras antagonist, however, fails to measurably disrupt signaling through either the MAPK or PI3K pathway. Consistently, cellular proliferation was unaffected as well. To understand this lack of signaling inhibition, we quantified the number of molecules of R11.1.6 expressed by the inducible cell lines and developed a simple mathematical model describing the competitive binding of Ras by R11.1.6 and Raf. This model supports a potential mechanism for the lack of biological effects that we observed, suggesting stoichiometric and thermodynamic barriers that should be overcome in pharmacologic efforts to directly compete with downstream effector proteins localized to membranes at very high effective concentrations. Mol Cancer Ther; 17(8); 1–8. ©2018 AACR.

  • ω‐Phthalimidoalkyl aryl ureas as potent and selective inhibitors of cholesterol esterase
    ChemMedChem (IF 3.009) Pub Date : 2018-07-13
    Florian M. Dato; Miriam Sheikh; Rocky Z. Uhl; Alexandra W. Schüller; Michaela Steinkrüger; Peter Koch; Jörg-Martin Neudörfl; Michael Gütschow; Bernd Goldfuss; Markus Pietsch

    Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure‐activity‐relationship study applying a small library of ω‐phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5‐bis(trifluoromethyl)phenyl group and the aromatic character of the ω‐phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so optimized compounds 2 (1‐(3,5‐bis(trifluoromethyl)phenyl)‐3‐(3‐(1,3‐dioxoisoindolin‐2‐yl)propyl)urea) and 21 (1‐(3,5‐bis(trifluoromethyl)‐phenyl)‐3‐(4‐(1,3‐dioxoisoindolin‐2‐yl)butyl)urea) exhibit dissociation constants (Ki) of 1‐19 µM on the two CEases and show either a competitive (2 at the human, 21 at the murine enzyme) or otherwise a non‐competitive mode of inhibition. Two related serine hydrolases, monoacylglycerol lipase and fatty acid amide hydrolase, were inhibited by ω‐phthalimidoalkyl aryl ureas to a lesser extent.

  • Exploiting Thiobarbituric Acid Scaffold for Antibacterial Activity
    ChemMedChem (IF 3.009) Pub Date : 2018-07-13
    Fernando Albericio; Anamika Sharma; Sikabe Noki; Sizwe J Zamisa; Heba Hazzah; Zainab M Almarhoon; Ayman El-Faham; Beatriz G de la Torre

    Thiobarbituric acid (TBA) has been considered as a privileged structure for developing antimicrobial agents. Diversity was obtained at position "N" and at "C‐5" through acylation, Schiff base formation, Knoevenagel condensation, thioamide, and enamine formation. The present work describes the synthesis of small libraries based on TBA moiety and above mentioned reactions. The preliminary antimicrobial activity screening for the prepared compounds against some selected bacteria (Gram +ve and Gram ‐ve) showed the best results with Boc‐Phe‐TBA derivative. These results could be useful for designing and building libraries based on other amino acids with distinct protecting groups.

  • Decoding the rich biological properties of noble gases: how well can we predict noble gas binding to diverse proteins?
    ChemMedChem (IF 3.009) Pub Date : 2018-07-12
    David Alan Winkler; Ira Katz; Géraldine Farjot; Aaron Thornton; Andrew Warden

    The chemically inert noble gases display a surprisingly rich spectrum of useful biological properties. Relatively little is known about molecular mechanisms behind these effects. It is clearly not feasible to conduct large numbers of pharmacological experiments on noble gases to identify activity. Computational studies of binding of noble gases and proteins can address this paucity of information and provide insight into mechanisms of action. We employed bespoke computational grid calculations to predict the positions of energy minima in the interactions of noble gases with diverse proteins. The method was validated by quantifying how well simulations could predict binding positions in 131 diverse protein x‐ray structures containing 399 Xe and Kr atoms. We found excellent agreement between calculated and experimental binding positions of noble gases. 94% of all crystallographic xenon atoms were within 1 Xe VdW diameter of a predicted binding site and 97% lay within 2 VdW diameters. 100% of crystallographic krypton atoms were within 1 Kr VdW diameter of a predicted binding site. We showed feasibility of large scale computational screening of all ~60,000 unique structures in the Protein Data Bank. This will elucidate biochemical mechanisms by which these novel 'atomic drugs' elicit their valuable biochemical properties and identify new medical uses.

  • The emerging role of copper-64 radiopharmaceuticals as cancer theranostics
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-07
    Alessandra Boschi, Petra Martini, Emilija Janevik-Ivanovska, Adriano Duatti

    Copper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly 64Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [64Cu2+] ions. For example, it has been demonstrated that administration of ionic [64Cu2+] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of 64Cu-radiopharmaceuticals in molecular imaging and cancer therapy.

  • NTM drug discovery: status, gaps and the way forward
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-07
    Mu-Lu Wu, Dinah B. Aziz, Véronique Dartois, Thomas Dick

    Incidence of pulmonary diseases caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing at an alarming rate, surpassing tuberculosis in many countries. Current chemotherapies require long treatment times and the clinical outcomes are often disappointing. There is an urgent medical need to discover and develop new, more-efficacious anti-NTM drugs. In this review, we summarize the current status of NTM drug development, and highlight knowledge gaps and scientific obstacles in NTM drug discovery. We propose strategies to reduce biological uncertainties and to begin to populate a NTM drug pipeline with attractive leads and drug candidates.

  • An operational model for GPCR homodimers and its application in the analysis of biased signaling
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-09
    Bin Zhou, Jesús Giraldo

    G-protein-coupled receptors are one of the most important protein superfamilies as drug targets in drug discovery programs. Their interactions with ligands are influenced by their homomerization. In this study, we propose an operational model for receptor homodimers, which includes constitutive receptor activity. Distinct functional response curves can be obtained from this model, which can satisfactorily depict typical complex experimental data as biphasic and bell-shaped curves. Operational parameters in the model can provide mechanistic explanations for observed functional complexity associated with the cooperativity and intrinsic efficacy of ligands. Because the model presented here is derived from the conceptual framework of operational models, it takes advantage of the body of knowledge coming from the widespread use of this type of modeling. The operational homodimer model can also explain the biased signaling dependent on ligand concentration. In conclusion, this operational homodimer model has a wide range of applications in pharmacological research.

  • The remarkable therapeutic potential of response-based dose individualisation in drug trials and patient care
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-12
    Chao Chen

    The FDA reported that most drugs are effective in only 25–62% of patients. Although many drugs require dose individualisation in clinical practice, dose-finding trials usually aim to identify an optimal dose for the patient population. Such a dose would be suboptimal for many patients. Simulations show that individualised dose titration, balancing efficacy against toxicity, can remarkably increase the response rate — doubling it in some situations. Dose titration in a clinical trial can efficiently establish the realistic expectations for the drug’s true utility in a trial setting that reflects clinical practice, as well as generate important knowledge to guide patient care through informative drug labels. This design answers key questions truly relevant to patient care that other designs cannot — will a patient benefit from a given therapy, to what extent and at what dose? Therefore, response-based dose titration should be considered for dose-finding trials, where appropriate, for drugs that will eventually be used this way in the clinic.

  • Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes
    Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-23
    Manish K. Tripathi, Kyle Doxtater, Fatemeh Keramatnia, Chidi Zacheaus, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan

    Long noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.

  • Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase
    Med. Chem. Commun. (IF 2.342) Pub Date : 2018-07-13
    Brooke Andrews, Richard Brian Dyer

    Lactate dehydrogenase (LDH) has recently garnered attention as an attractive target for cancer therapies, owing to the enzyme’s critical role in cellular metabolism. Current inhibition strategies, employing substrate or cofactor analogues, are insufficiently specific for use as pharmaceutical agents. The possibility of allosteric inhibition of LDH was postulated on the basis of theoretical docking studies of a small molecule inhibitor to LDH. The present study examined structural analogues of this proposed inhibitor to gauge its potency and attempt to elucidate the molecular mechanism of action. These analogues display encouraging in vitro inhibition of porcine heart LDH, including micromolar Ki values and a maximum inhibition of up to 50% in the steady state. Furthermore, Michaelis-Menten kinetics and fluorescence data both suggest the simple, acetaminophen derivatives are non-competitive in binding to the enzyme. Kinetic comparisons of a panel of increasingly decorated structural analogues imply that the binding is specific, and the small molecule core provides a privileged scaffold for further pharmaceutical development of a novel, allosteric drug.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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