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  • Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-21
    Mohammad Zarei; Javier Pizarro-Delgado; Emma Barroso; Xavier Palomer; Manuel Vázquez-Carrera

    Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease (NAFLD), is defined as the presence of hepatic steatosis with inflammation, hepatocyte injury, and different degrees of fibrosis. Although NASH affects 2–5% of the global population, no drug has been specifically approved to treat the disease. Fibroblast growth factor 21 (FGF21) and its analogs have emerged as a potential new therapeutic strategy for the treatment of NASH. In fact, FGF21 deficiency favors the development of steatosis, inflammation, hepatocyte damage, and fibrosis in the liver, whereas administration of FGF21 analogs ameliorates NASH by attenuating these processes. We review mechanistic insights into the beneficial and potential side effects of therapeutic approaches targeting FGF21 for the treatment of NASH.

  • Identifying Missing Biosynthesis Enzymes of Plant Natural Products
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-21
    Thomas Dugé de Bernonville; Nicolas Papon; Marc Clastre; Sarah E. O’Connor; Vincent Courdavault

    Elucidating plant-specialized biosynthetic pathways has always constituted a laborious task, notably for natural products with high pharmaceutical values. Here, we discuss emerging omics-based strategies that facilitate the identification of genes from these complex metabolic pathways, paving the way to engineered supplies of these compounds through synthetic biology approaches.

  • Immunotherapy for Malignant Glioma: Current Status and Future Directions
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-21
    Hongxiang Wang; Tao Xu; Qilin Huang; Weilin Jin; Juxiang Chen

    Glioma is the most common intracranial primary malignancy, with limited treatment options and a poor overall survival (OS). Immunotherapy has been used successfully in various cancers, leading to the development of similar therapies that activate the patient’s immune system to eliminate glioma. In this review, we introduce the diverse immunotherapeutic approaches available for treating glioma, highlighting the successes and challenges resulting from current clinical trials. Additionally, we emphasize the effect of multiple clinical factors on immunotherapy to help optimize individualized treatment regimens. Finally, we also highlight several novel concepts and technologies that could be used to design new and/or improve existing immunotherapies. Such approaches will delineate a new blueprint for glioma treatment.

  • Opioid-Induced Adaptations of cAMP Dynamics in the Nucleus Accumbens
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-18
    Sarah Zych; Christopher P. Ford

    To investigate how opioid exposure alters dopamine (DA) responses in medium spiny neurons (MSNs), Muntean et al. used a novel cAMP sensor to track cAMP dynamics and report a coordinated effort of adaptations in D1- and D2-MSNs to integrate DA inputs and shift signaling strengths in various states of opioid dependence.

  • Proteomics and Imaging in Crohn’s Disease: TAILS of Unlikely Allies
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-14
    Barbara Mainoli; Simon Hirota; Laura E. Edgington-Mitchell; Cathy Lu; Antoine Dufour

    Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disease (IBD) that may be marked by debilitating symptoms of abdominal pain and obstruction. The etiology and pathogenesis of the disease are not fully understood, and treatment with corticosteroids, biologics, and surgical intervention are the usual therapeutic options. Diagnosis, disease activity, and therapeutic response are currently assessed by endoscopy, cross-sectional imaging, and biomarkers. However, challenges remain regarding the efficacy of the drugs and safety of these imaging techniques. There are also limitations with current clinical and laboratory tools for diagnosis, disease progression, and treatment response. Here, we discuss how the integration of proteomics and activity-based probes, along with intestinal ultrasound, an easily repeatable and well-tolerated diagnostic imaging modality, can address these challenges and may provide a novel precision medicine-based approach for the treatment of CD.

  • Development and Regulation of Gene and Cell-Based Therapies in Europe: A Quantification and Reflection
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-13
    Renske M.T. ten Ham; Anke M. Hövels; Olaf H. Klungel; Hubert G.M. Leufkens; Andre W. Broekmans; Jarno Hoekman

    Gene and cell-based therapies (GCTs) are said to hold great promise as treatments for previously untreatable and high-burden diseases. Here, we provide insight into GCT development and regulation activities in Europe, quantify clinical and regulatory success, and compare these with other medicinal products in order to reflect on regulatory changes and challenges.

  • Enhancing Choice and Outcomes for Therapeutic Trials in Chronic Pain: N-of-1 + Imaging (+ i)
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-09
    David Borsook; Jaymin Upadhyay; Richard Hargreaves; Tor Wager

    The attrition of novel analgesic drugs in the clinic can be attributed in the main to two factors: failure of preclinical research findings translating into human pain conditions, and a drop-off of efficacy between proof-of-concept (i.e., Phase II trials) and pivotal, confirmatory (Phase III trials) testing. In order to enhance the efficiency of the clinical drug evaluation process and determine rapidly whether a potential therapeutic candidate gives pain relief, by modulating central pain neurobiology, we propose a ‘pre-proof-of-concept’ approach, in which an efficacy assessment is performed in a single individual (N-of-1) using subjective clinical pain assessments supported by objective validated functional neuroimaging measures. Using an N-of-1 + i methodology, clinical- and neuroimaging-based metrics can be quantified under conditions of drug versus placebo or drug versus current standard of care conditions.

  • Ropinirole, a New ALS Drug Candidate Developed Using iPSCs
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-08
    Hideyuki Okano; Daisuke Yasuda; Koki Fujimori; Satoru Morimoto; Shinichi Takahashi

    Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs – ropinirole (ROPI), retigabine, and bosutinib – have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.

  • Drug Screen Tugs at Common Thread for Repeat Disorders
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2020-01-08
    Kaalak Reddy; John Douglas Cleary; J. Andrew Berglund

    Repeat-associated non-ATG (RAN) translation is emerging as a driver of pathogenesis in microsatellite expansion disorders. Green and colleagues recently identified several candidate RAN translation inhibitors from a high-throughput small-molecule screen for fragile X tremor ataxia syndrome. Their study establishes a path forward for identifying inhibitors of RAN translation for multiple disorders.

  • Insight into the Structural Features of TSPO: Implications for Drug Development
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-18
    Jean-Jacques Lacapere; Luminita Duma; Stephanie Finet; Michael Kassiou; Vassilios Papadopoulos

    The translocator protein (TSPO), an 18-kDa transmembrane protein primarily found in the outer mitochondrial membrane, is evolutionarily conserved and widely distributed across species. In mammals, TSPO has been described as a key member of a multiprotein complex involved in many putative functions and, over the years, several classes of ligand have been developed to modulate these functions. In this review, we consider the currently available atomic structures of mouse and bacterial TSPO and propose a rationale for the development of new ligands for the protein. We provide a review of TSPO monomeric and oligomeric states and their conformational flexibility, together with ligand-binding site and interaction mechanisms. These data are expected to help considerably the development of high-affinity ligands for TSPO-based therapies or diagnostics.

  • Strategies for the CRISPR-Based Therapeutics
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-17
    Bin Li; Yuyu Niu; Weizhi Ji; Yizhou Dong

    The CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing technology is an emerging RNA-guided nuclease system initially identified from the microbial adaptive immune systems. In recent years, the CRISPR system has been reprogrammed to target specific regions of the eukaryotic genome and has become a powerful tool for genetic engineering. Researchers have explored many approaches to improve the genome editing activity of the CRISPR–Cas system and deliver its components both ex vivo and in vivo. Moreover, these strategies have been applied to genome editing in preclinical research and clinical trials. In this review, we focus on representative strategies for regulation and delivery of the CRISPR–Cas system, and outline current therapeutic applications in their clinical translation.

  • Overcoming the Brain Barriers: From Immune Cells to Nanoparticles
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-12
    Marc Charabati; Jean-Michel Rabanel; Charles Ramassamy; Alexandre Prat

    Nanoparticulate carriers, often referred to as nanoparticles (NPs), represent an important pharmacological advance for drug protection and tissue-specific drug delivery. Accessing the central nervous system (CNS), however, is a complex process regulated by mainly three brain barriers. While some leukocyte (i.e., immune cell) subsets are equipped with the adequate molecular machinery to infiltrate the CNS in physiological and/or pathological contexts, the successful delivery of NPs into the CNS remains hindered by the tightness of the brain barriers. Here, we present an overview of the three major brain barriers and the mechanisms allowing leukocytes to migrate across each of them. We subsequently review different immune-inspired and -mediated strategies to deliver NPs into the CNS. Finally, we discuss the prospect of exploiting leukocyte trafficking mechanisms for further progress.

  • Oligonucleotides to the (Gene) Rescue: FDA Approvals 2017–2019
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-10
    Jacqueline Rüger, Silvia Ioannou, Daniela Castanotto, Cy A. Stein

    Four decades have passed since oligonucleotides were first used to manipulate gene expression. There were few FDA approvals prior to 2016, mostly of drugs that eventually exhibited poor performance in the market. The aura of their younger siRNA relatives had also faded during the past 15 years. However, several FDA approvals have occurred in the past 4 years, restoring hope that a new era has dawned in oligonucleotide/siRNA clinical therapeutics. Here, we review the field of oligonucleotide therapeutics and provide an update on FDA approvals of oligonucleotides from 2017 until the second quarter of 2019. We take into consideration the ethical issues looming over the still somewhat limited efficacy of these molecules, the toxicity of treatment, and the exorbitant cost of these therapeutic agents, which limits accessibility for many.

  • Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-10
    Yang Liu, Pan Zheng

    A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment.

  • Targeting Bacterial Genomes for Natural Product Discovery
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-07
    Edward Kalkreuter, Guohui Pan, Alexis J. Cepeda, Ben Shen

    Bacterial natural products (NPs) and their analogs constitute more than half of the new small molecule drugs developed over the past few decades. Despite this success, interest in natural products from major pharmaceutical companies has decreased even as genomics has uncovered the large number of biosynthetic gene clusters (BGCs) that encode for novel natural products. To date, there is still a lack of universal strategies and enabling technologies to discover natural products at scale and speed. This review highlights several of the opportunities provided by genome sequencing and bioinformatics, challenges associated with translating genomes into natural products, and examples of successful strain prioritization and BGC activation strategies that have been used in the genomic era for natural product discovery from cultivatable bacteria.

  • Targeting Mutant KRAS for Immunogenic Cell Death Induction
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-12-06
    Lorenzo Galluzzi

    Although somatic KRAS mutations are common in human tumors, no inhibitor of mutant KRAS was clinically available until recently. Canon and colleagues describe the ability of a clinically available KRASG12C inhibitor to drive immunogenic cancer cell death, thus constituting a promising combinatorial partner for immune checkpoint blockers.

  • Inhibiting Heat Shock Factor 1 in Cancer: A Unique Therapeutic Opportunity
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-11
    Bushu Dong, Alex M. Jaeger, Dennis J. Thiele

    The ability of cancer cells to cope with stressful conditions is critical for their survival, proliferation, and metastasis. The heat shock transcription factor 1 (HSF1) protects cells from stresses such as chemicals, radiation, and temperature. These properties of HSF1 are exploited by a broad spectrum of cancers, which exhibit high levels of nuclear, active HSF1. Functions for HSF1 in malignancy extend well beyond its central role in protein quality control. While HSF1 has been validated as a powerful target in cancers by genetic knockdown studies, HSF1 inhibitors reported to date have lacked sufficient specificity and potency for clinical evaluation. We review the roles of HSF1 in cancer, its potential as a prognostic indicator for cancer treatment, evaluate current HSF1 inhibitors and provide guidelines for the identification of selective HSF1 inhibitors as chemical probes and for clinical development.

  • Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-08
    Sean P. Moran, James Maksymetz, P. Jeffrey Conn

    Muscarinic acetylcholine receptors (mAChR) play important roles in regulating complex behaviors such as cognition, movement, and reward, making them ideally situated as potential drug targets for the treatment of several brain disorders. Recent advances in the discovery of subtype-selective allosteric modulators for mAChRs has provided an unprecedented opportunity for highly specific modulation of signaling by individual mAChR subtypes in the brain. Recently, mAChR allosteric modulators have entered clinical development for Alzheimer’s disease (AD) and schizophrenia, and have potential utility for other brain disorders. However, mAChR allosteric modulators can display a diverse array of pharmacological properties, and a more nuanced understanding of the mAChR will be necessary to best translate preclinical findings into successful clinical treatments.

  • A Third Shot at EGFR: New Opportunities in Cancer Therapy
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-06
    Salvador Guardiola, Monica Varese, Macarena Sánchez-Navarro, Ernest Giralt

    Epidermal growth factor receptor (EGFR) inhibitors were among the first type of targeted agents discovered in cancer and currently constitute the standard of care for a wide range of lung and colon malignancies. However, the therapeutic progress achieved with these drugs has been accompanied by the identification of an ever-increasing number of acquired resistance mechanisms that inevitably appear in nearly all patients. Increased knowledge on EGFR biochemistry, cellular crosstalk, and resistance pathways provides an opportunity to establish effective combination therapies and discover novel-acting inhibitors that prevent or overcome therapeutic resistance. One such strategy is the selective blockade of circulating growth factors such as EGF. In this review, we address the uses and limitations of approved EGFR inhibitors and explore the potential of drug combinations and new third avenues to block the activation of the EGFR.

  • Dichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-06
    Pedro Gomes, Helena Leal, Alexandrina F. Mendes, Flávio Reis, Cláudia Cavadas

    Sirtuins (SIRT1–7), a class of NAD+-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirtuins act as ‘double-edged swords’. Here, we provide an integrated overview of the different findings on the role of mammalian sirtuins in neurodegenerative and cardiometabolic disorders and attempt to dissect the reasons behind these different effects. Finally, we discuss how addressing these obstacles may provide a better understanding of the complex sirtuin biology and improve the likelihood of identifying effective and selective drug targets for a variety of human disorders.

  • Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-06
    Pooja Gopal, Gerhard Grüber, Véronique Dartois, Thomas Dick

    Inclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this remarkable effect in patients despite displaying poor potency against Mycobacterium tuberculosis (Mtb) in vitro. The pharmacological basis for the in vivo sterilizing activity of the drug has remained obscure and its bacterial target controversial. Recently it was shown that PZA penetrates necrotic caseous TB lung lesions and kills nongrowing, drug-tolerant bacilli. Furthermore, it was uncovered that PZA inhibits bacterial Coenzyme A biosynthesis. It may block this pathway by triggering degradation of its target, aspartate decarboxylase. The elucidation of the pharmacological and molecular mechanisms of PZA provides the basis for the rational discovery of the next-generation PZA with improved in vitro potency while maintaining attractive pharmacological properties.

  • Piezo Ion Channels in Cardiovascular Mechanobiology
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-05
    Dominique Douguet, Amanda Patel, Aimin Xu, Paul M. Vanhoutte, Eric Honoré

    Mechanotransduction has a key role in vascular development, physiology, and disease states. Piezo1 is a mechanosensitive (MS) nonselective cationic channel that occurs in endothelial and vascular smooth muscle cells. It is activated by shear stress associated with increases in local blood flow, as well as by cell membrane stretch upon elevation of blood pressure. Here, we briefly review the pharmacological modulators of Piezo and discuss current understanding of the role of Piezo1 in vascular mechanobiology and associated clinical disorders, such as atherosclerosis and hypertension. Ultimately, we believe that this research will help identify novel therapeutic strategies for the treatment of vascular diseases.

  • Why Are Some Driver Mutations Rare?
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-05
    Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang

    Understanding why driver mutations that promote cancer are sometimes rare is important for precision medicine since it would help in their identification. Driver mutations are largely discovered through their frequencies. Thus, rare mutations often escape detection. Unlike high-frequency drivers, low-frequency drivers can be tissue specific; rare drivers have extremely low frequencies. Here, we discuss rare drivers and strategies to discover them. We suggest that allosteric driver mutations shift the protein ensemble from the inactive to the active state. Rare allosteric drivers are statistically rare since, to switch the protein functional state, they cooperate with additional mutations, and these are not considered in the patient cancer-specific protein sequence analysis. A complete landscape of mutations that drive cancer will reveal tumor-specific therapeutic vulnerabilities.

  • Phosphodiesterase Type 4 Inhibition in CNS Diseases
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-05
    Arjan Blokland, Pim Heckman, Tim Vanmierlo, Rudy Schreiber, Dean Paes, Jos Prickaerts

    Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABI). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects.

  • Charting a TRP to Novel Therapeutic Destinations for Kidney Diseases
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-11-05
    Juan Lorenzo Pablo, Anna Greka

    Ion channels are critical to kidney function, and their dysregulation leads to several distinct kidney diseases. Of the diversity of ion channels in kidney cells, the transient receptor potential (TRP) superfamily of proteins plays important and varied roles in both maintaining homeostasis as well as in causing disease. Recent work showed that TRPC5 blockers could successfully protect critical components of the kidney filter both in vitro and in vivo, thus revealing TRPC5 as a tractable therapeutic target for focal and segmental glomerulosclerosis (FSGS), a common cause of kidney failure. Human genetics point to three additional TRP channels as plausible therapeutic targets: TRPC6 in FSGS, PKD2 in polycystic kidney disease, and TRPM6 in familial hypomagnesemia with secondary hypocalcemia (HSH). We conclude that targeting TRP channels could pave the way for much needed therapies for kidney diseases.

  • Combating Human Pathogens and Cancer by Targeting Phosphoinositides and Their Metabolism
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-10-31
    Thanh Kha Phan, Guneet K. Bindra, Scott A. Williams, Ivan K.H. Poon, Mark D. Hulett

    Pathogens and tumor cells have adopted various adept strategies to evade immunosurveillance and promote their growth and survival. There has been substantial evidence demonstrating phosphoinositide lipids and their modifying enzymes as essential host targets that are often hijacked by pathogens and tumor cells. The common dependence of pathogen virulence and tumor progression on phosphoinositides presents an exciting disease-combating potential, particularly combinatorial therapeutics. While traditional approaches to pharmacologically inhibit phosphoinositide-metabolizing enzymes has shown some promise, the direct targeting of phosphoinositides has recently emerged as a novel therapeutic strategy. Our review provides a current picture of the role of phosphoinositides during pathogen virulence and tumorigenesis as well as a thorough discussion on promises, challenges, and new perspectives of phosphoinositide-targeting drug development.

  • The B7x Immune Checkpoint Pathway: From Discovery to Clinical Trial
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-10-31
    Peter John, Yao Wei, Weifeng Liu, Meirong Du, Fangxia Guan, Xingxing Zang

    B7x (B7 homolog x, also known as B7-H4, B7S1, and VTCN1) was discovered by ourselves and others in 2003 as the seventh member of the B7 family. It is an inhibitory immune checkpoint of great significance to human disease. Tissue-expressed B7x minimizes autoimmune and inflammatory responses. It is overexpressed in a broad spectrum of human cancers, where it suppresses antitumor immunity. Further, B7x and PD-L1 tend to have mutually exclusive expression in cancer cells. Therapeutics targeting B7x are effective in animal models of cancers and autoimmune disorders, and early-phase clinical trials are underway to determine the efficacy and safety of targeting B7x in human diseases. It took 15 years moving from the discovery of B7x to clinical trials. Further studies will be necessary to identify its receptors, reveal its physiological functions in organs, and combine therapies targeting B7x with other treatments.

  • The Landscape of Atypical and Eukaryotic Protein Kinases
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-10-31
    Georgi K. Kanev, Chris de Graaf, Iwan J.P. de Esch, Rob Leurs, Thomas Würdinger, Bart A. Westerman, Albert J. Kooistra

    Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.

  • Pharmacogenomic Approach to Antimyopia Drug Development: Pathways Lead the Way
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-10-30
    Tatiana V. Tkatchenko, Andrei V. Tkatchenko

    Myopia is the most common eye disorder in the world which is caused by a mismatch between the optical power of the eye and its excessively long axial length. Recent studies revealed that the regulation of the axial length of the eye occurs via a complex signaling cascade, which originates in the retina and propagates across all ocular tissues to the sclera. The complexity of this regulatory cascade has made it particularly difficult to develop effective antimyopia drugs. The current pharmacological treatment options for myopia are limited to atropine and 7-methylxanthine, which have either significant adverse effects or low efficacy. In this review, we focus on the recent advances in genome-wide studies of the signaling pathways underlying myopia development and discuss the potential of systems genetics and pharmacogenomic approaches for the development of antimyopia drugs.

  • Mouse models of Huntington's disease.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-01-24
    Liliana B Menalled,Marie-Françoise Chesselet

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In 1993 the mutation that causes HD was identified as an unstable expansion of CAG repeats in the IT15 gene. Since then one of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular and cellular abnormalities produced by the mutation. In addition, these models have made it possible to test different pharmacological approaches to delay the onset or slow the progression of HD. In this article, insights gained from mouse models towards the understanding of HD and the design of new therapeutic strategies are discussed.

  • Towards a revised nomenclature for P1 and P2 receptors.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 1997-03-01
    B B Fredholm,M P Abbracchio,G Burnstock,G R Dubyak,T K Harden,K A Jacobson,U Schwabe,M Williams

  • Adenosine receptor ligands: differences with acute versus chronic treatment.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 1996-03-01
    K A Jacobson,D K von Lubitz,J W Daly,B B Fredholm

    Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This 'effect inversion' is discussed here by Ken Jacobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage.

  • Advancing Drug Discovery via Artificial Intelligence.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2019-08-28
    H C Stephen Chan,Hanbin Shan,Thamani Dahoun,Horst Vogel,Shuguang Yuan

  • Adenosine A3 receptors: novel ligands and paradoxical effects.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 1998-07-04
    K A Jacobson

    The physiological role of the adenosine A3 receptor is being investigated using newly synthesized, selective ligands. Recently, in addition to agonists, selective antagonists have been developed that belong to three distinct, non-purine chemical classes: flavonoids, 1,4-dihydropyridine derivatives (e.g. MRS1191, which is 1300-fold selective for human adenosine A3 vs A1/A2A receptors, with a Ki value of 31 nM) and the triazoloquinazolines (e.g. MRS1220, which has a Ki value of 0.65 nM). The A3 receptor has proven enigmatic in terms of antagonist ligand specificity, coupling to second messengers, and biological effects in the CNS, inflammatory system and cardiovascular system. A3 receptors are also potentially involved in apoptosis. It appears that intense, acute activation of A3 receptors acts as a lethal input to cells, while low concentrations of A3 receptor agonists protect against apoptosis. Here, Kenneth Jacobson describes how A3 receptor agonists might be useful in treating inflammatory conditions, possibly through their inhibition of tumour necrosis factor alpha (TNF-alpha) release, which has been shown in macrophages. A3 receptor antagonists might be useful in treating asthma or acute brain ischaemia. Recently, the versatility of A3 receptor agonists, administered either before or during ischaemia, in eliciting potent cardioprotection has been shown.

  • Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2017-03-12
    Jason Munguia,Victor Nizet

    The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms.

  • Interview with Fiona Marshall.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2012-09-27
    Fiona Marshall

  • An interview with P. Jeffrey Conn.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2012-04-11
    P Jeffrey Conn

  • An interview with Robert J. Lefkowitz.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2012-03-10
    Robert J Lefkowitz

  • An interview with Stewart Adams.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2012-02-18
    Stewart Adams

  • 5-hydroxytryptamine and cardiovascular regulation.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2008-12-17
    Andrew G Ramage,Carlos M Villalón

    All 5-hydroxytryptamine (5-HT; serotonin) receptors, except the 5-HT6 type, have been shown to be involved in cardiovascular regulation. In the periphery, 5-HT is stored in platelets, but the physiological role of 5-HT in the regulation of vascular tone (as opposed to its role in coagulation) remains unclear. However, central 5-HT1A, 5-HT3 and 5-HT7 receptors do play a physiological part in the regulation of cardiovascular reflexes, controlling changes in parasympathetic (vagal) drive to the heart. These reflexes also affect activity in the sympathetic nervous system, which itself can be inhibited by central 5-HT(1A) receptors to cause falls in blood pressure and excited by 5-HT2 receptors to cause rises in blood pressure. The physiological role of these receptors in the central regulation of the sympathetic nervous system is unclear, although 5-HT2 receptors could be involved in the development of deoxycorticosterone-acetate-salt hypertension, which is probably related to their role in the control of vasopressin release.

  • A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2008-12-17
    Madeleine V King,Charles A Marsden,Kevin C F Fone

    The serotonergic system is implicated in the neurobiological control of learning and memory, both in healthy individuals and pathological disorders, although the underlying mechanisms remain elusive. After the cloning and characterization of serotonin, or 5-hydroxytryptamine (5-HT), receptors and the resultant development of selective agonist and antagonist compounds and transgenic receptor-knockout mice, our understanding of the role of various serotonin receptors in learning and memory has improved. 5-HT(1A), 5-HT4 and 5-HT6 receptors are densely expressed in brain regions innervated by serotonergic projections from the raphe nuclei and are associated with learning and memory. Here, we review the evidence that compounds acting on these receptors can have positive effects on learning and memory, and we discuss the potential mechanisms involved. This information raises the possibility that such compounds could be developed as adjunct therapeutics with existing treatments to improve learning and memory deficits, which are core symptoms of Alzheimer's disease, schizophrenia and depression.

  • 更新日期:2019-11-01
  • Update on human alpha1-adrenoceptor subtype signaling and genomic organization.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2004-11-24
    K Ashley Hawrylyshyn,Gregory A Michelotti,Francis Cogé,Sophie-Pénélope Guénin,Debra A Schwinn

    Alpha1-adrenoceptors are G-protein-coupled receptors that bind catecholamines. Sixteen distinct human alpha1A-adrenoceptor isoforms have been identified from human tissues, including five full-length and 11 truncated versions. An updated scheme for the identification of alpha1A-adrenoceptor splice variants is proposed. Given the established roles of alpha1-adrenoceptors in benign prostatic hyperplasia, myocardial hypertrophy and other cardiovascular disorders, elucidation of the biological significance of the signaling diversity and potential pharmacological roles of alpha1A-adrenoceptor splice variants are important areas of future research.

  • The structure of GRK2-G beta gamma complex: intimate association of G-protein signaling modules.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2004-04-27
    Tohru Kozasa

    G-protein-mediated signaling is the most widely used signaling mechanism in cells and its regulation is crucial for various physiological functions. G-protein-coupled receptor (GPCR) kinases (GRKs) are involved in the desensitization of GPCR signals. Recently, the X-ray crystal structure of GRK2 complexed with G beta gamma was demonstrated and revealed the intimate association of three important signaling modules with G beta gamma to regulate GRK2 activity.

  • Herbal alkaloid tetrandrine: fron an ion channel blocker to inhibitor of tumor proliferation.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2004-04-03
    Gang Wang,José R Lemos,Costantino Iadecola

  • From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2004-01-16
    C Guin Ting Wong,K Michael Gibson,O Carter Snead

    gamma-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is formed primarily from the precursor gamma-aminobutyric acid (GABA). The properties of GHB suggest that it has a neuromodulatory role in the brain and has the ability to induce several pharmacological and behavioral effects. GHB has been used clinically as an anesthetic and to treat alcoholism and narcolepsy. Furthermore, GHB has emerged recently as a major recreational drug of abuse. GHB appears to have dual mechanisms of action in the brain. Biochemical data suggest that the intrinsic neurobiological activity of GHB might be mediated through the GHB receptor, which is separate and distinct from the GABA(B) receptor. However, many of the pharmacological and clinical effects of exogenously administered GHB, including the properties of addiction, tolerance, withdrawal and intoxication, are probably mediated via the GABA(B) receptor, where GHB might act both directly as a partial agonist and indirectly through GHB-derived GABA.

  • Is frequent dosing with ecstasy a risky business for dopamine-containing neurons?
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-06-26
    Esther O'Shea,M Isabel Colado

    Over the past 20 years 3,4-methylenedioxymethamphetamine (MDMA; also known as 'ecstasy') has become a widely used recreational drug of abuse. However, studies have indicated that it is neurotoxic to serotonergic nerve terminals in rats and non-human primates and dopaminergic nerve terminals in mice. Recently, this tenet has been questioned following a study suggesting that MDMA can cause toxicity to dopamine-containing neurons in monkeys. In this article, the factors contributing to this change in neurotoxic profile are discussed.

  • The Wnt pathway, cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer's disease?
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-05-28
    Andrea Caricasole,Agata Copani,Alessandra Caruso,Filippo Caraci,Luisa Iacovelli,Maria Angela Sortino,Georg C Terstappen,Ferdinando Nicoletti

    Beta-amyloid protein (betaAP) is thought to cause neuronal loss in Alzheimer's disease (AD). Applied to neurons in culture, betaAP induces neuronal death and hyperphosphorylation of tau protein, which forms neurofibrillary tangles (NFTs) in AD brains. Neurons also undergo rapid apoptotic death following reactivation of a mitotic cycle. However, the molecular events that determine the fate of neurons challenged with betaAP (apoptotic death, formation of NFTs and survival) are unclear. We discuss a scenario for the pathogenesis of AD. This links betaAP-induced changes to the Wnt signaling pathway that promotes proliferation of progenitor cells and directs cells into a neuronal phenotype during brain development. We propose that betaAP-mediated facilitation of mitogenic Wnt signaling activates unscheduled mitosis in differentiated neurons. Furthermore, late downregulation of Wnt signaling by betaAP might lead to NFT formation. We propose that drugs that both inhibit the cell cycle and rescue Wnt activity could provide novel AD therapeutics.

  • 5-HT(1)-like receptor agonists and the pathophysiology of migraine.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 1989-05-01
    P R Saxena,M D Ferrari

    Recently, AG-25086 and GR-43175 have been reported to be highly effective in aborting acute migraine attacks. These compounds seem selectively to stimulate a sub-population of 5-HT(1)-like receptors to inhibit noradrenaline release from certain sympathetic neurovascular terminals, to contract dog saphenous vein and dog, monkey and human basilar arteries, and to decrease the arteriovenous anastomotic component of carotid blood flow in the cat. GR-43175 neither has any antinociceptive effect nor crosses the blood-brain barrier. Pramod Saxena and Michel Ferrari review the clinical effectiveness of these 5-HT(1)-like receptor agonists and their selective pharmacology, both of which strongly suggest that excessive dilatation in the extracerebral cranial (scalp and/or dural) vasculature is an integral part of the pathophysiology of migraine.

  • In vitro and pharmacophore insights into CYP3A enzymes.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-04-23
    Sean Ekins,David M Stresser,J Andrew Williams

    The cytochrome P450 3A (CYP3A) enzymes have a major role in the metabolism of drugs in humans. Their wide substrate specificity and induction by a vast array of structurally diverse compounds presents the possibility of metabolic drug-drug interactions. Understanding the enzymes themselves is crucial. Over the past decade, this has occurred mostly with in vitro studies, although more recent approaches incorporate computational models to predict CYP inhibition and substrate potential. The three-dimensional displacement, or pharmacophore, of chemical features in space that are derived from inhibition data have produced pharmacophores for CYP3A4, CYP3A5 and CYP3A7, and provide new insights into ligand binding for each enzyme.

  • Viral leads for chemokine-modulatory drugs.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-03-12
    Morten Lindow,Hans Rudolf Lüttichau,Thue W Schwartz

    The chemokine system, which controls leukocyte trafficking, provides several potentially very attractive anti-inflammatory drug targets. However, the complexity and redundancy of this system makes it very difficult to exploit through classical drug discovery. Despite this, viruses have millions of years of experience in manipulating this system. For example, virally encoded "biopharmaceuticals"--chemokines and chemokine binding proteins--demonstrate the effectiveness of blocking a carefully selected group of chemokine receptors and how the local immune response can be changed from one dominated by Th1 cells to one dominated by Th2 cells by targeting specific chemokine receptors. The crucial importance of the binding of chemokines to glycosaminoglycans to produce their effects is also highlighted by viruses that produce binding proteins to disrupt the gradient of chemokines, which guides the direction leukocyte migration.

  • Useful G-protein-coupled receptor websites.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-03-05
    B K Rana,P A Insel

  • Principles: extending the utility of [35S]GTP gamma S binding assays.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-02-01
    Graeme Milligan

    Ligand regulation of the binding of [35S]GTPgammaS is one of the most widely used methods to measure receptor activation of heterotrimeric G proteins. However, until recently this method was largely restricted to receptors that interact with members of the family of pertussis-toxin-sensitive G proteins. Here, the reasons for this restriction are discussed and recent approaches that have extended the utility of this method such that it is now suitable for analysis of the activation of any heterotrimeric G protein are reviewed.

  • Pharmacological effects of garlic extract.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-02-01
    Ruomei Qi,Zhengang Wang

  • Interfering with leukocyte rolling--a promising therapeutic approach in inflammatory skin disorders?
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2003-02-01
    Wolf-H Boehncke,Michael P Schön

    Many novel anti-inflammatory compounds have been derived from research tools designed to better understand the complex process of leukocyte extravasation at sites of inflammation. Given that selectin-mediated rolling is the crucial initial step of leukocyte localization to the skin, specific interference with this mechanism is a particularly attractive target to treat cutaneous inflammation. Recently, several exciting advances have been reported aimed at selective interference with specific target molecules crucially involved in leukocyte rolling.

  • Techniques: applications of the nerve-bouton preparation in neuropharmacology.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-12-25
    Norio Akaike,Andrew J Moorhouse

    Single mammalian neurons can be isolated with adherent functional synaptic terminals using an enzyme-free, mechanical dissociation procedure. This allows investigations of the effects of presynaptic modulators of synaptic transmission with unprecedented ease and accuracy. Furthermore, single presynaptic terminals and boutons can be visualized using fluorescent markers and can also be focally stimulated with electrical pulses. In this article, the isolated-nerve-adherent-synaptic-bouton preparation and some examples of its general properties and uses are discussed.

  • Techniques: fruit flies as models for neuropharmacological research.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-12-25
    Hari Manev,Nikola Dimitrijevic,Svetlana Dzitoyeva

    An unlikely animal model is gaining popularity in neuropharmacological research: the 2-mm fruit fly (Drosophila melanogaster). Drugs have been administered to adult flies in their food and, more recently, via gasses and injections. Pharmacological tools have introduced behavioral alterations in Drosophila reminiscent of human behavior, rescued flies from gene-alteration-triggered neuropathologies, and triggered gene silencing. Combined, these methods hold promise for significant neuropharmacological advancement.

  • Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors?
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-12-25
    Elodie Archer,Bernard Maigret,Chantal Escrieut,Lucien Pradayrol,Daniel Fourmy

    Molecular modelling is of major help to understand structure-function data on G-protein-coupled receptors (GPCRs). Since the first determination of the structure of rhodopsin, at high resolution, the view has emerged that it will be now easy to automatically obtain realistic models for any GPCR by homology modeling. Our experience on cholecystokinin CCK(1) receptor modelling together with available data on other GPCRs leads us to rule out this opinion. We believe that construction of realistic models of certain GPCRs still remains time-consuming and requires many refinements of the models in close association with experiments. This conclusion has important consequences for modelling orphan GPCRs.

  • Emerging roles for orphan G-protein-coupled receptors in the cardiovascular system.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-12-25
    Sidath Katugampola,Anthony Davenport

    Despite current drug therapies, including those that target enzymes, channels and known G-protein-coupled receptors (GPCRs), cardiovascular disease remains the major cause of ill health, which suggests that other transmitter systems might be involved in this disease. In humans, approximately 175 genes have been predicted to encode 'orphan' GPCRs, where the endogenous ligand is not yet known. As a result of intensive screening using 'reverse pharmacology', an increasing number of orphan receptors are being paired with their cognate ligands, many of which are peptides. The existence of some of these peptides such as urotensin-II and relaxin had been known for some time but others, including ghrelin and apelin, represent novel sequences. The pharmacological characterization of these emerging peptide-receptor systems is a tantalising area of cardiovascular research, with the prospect of identifying new therapeutic targets.

  • Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces.
    Trends Pharmacol. Sci. (IF 11.523) Pub Date : 2002-12-25
    Rudi Busse,Ingrid Fleming

    Endothelial cells, which are situated at the interface between blood and the vessel wall, have a crucial role in controlling vascular tone and homeostasis, particularly in determining the expression of pro-atherosclerotic and anti-atherosclerotic genes. Many of these effects are mediated by changes in the generation and release of endothelium-derived autacoids [from the Greek autos (self) and akos (remedy)], which are generally short-lived and locally acting. In vivo, endothelial cells are constantly subjected to mechanical stimulation, which in turn determines the acute production of autacoids and the levels of autacoid-producing enzymes.

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