One-Size-Fits-All Dosing in Oncology Wastes Money, Innovation and Lives Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-21 David C. Norris
Failure to individualize drug dosing may waste 50% of the value of pharmaceutical innovation coming off the bench, driving the unacceptable failure rates of drug development programs and unsustainable drug costs. An immense opportunity is thus presented to investors in pharmaceutical innovation who are willing to develop and field innovative Phase 1 trial methodologies that solve this problem. The principle of Dose Titration Algorithm Tuning (DTAT) offers a reasoned strategy for accomplishing this. Figure options
Recent advances in bacteriophage-based methods for bacteria detection Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-20 Łukasz Richter, Marta Janczuk-Richter, Joanna Niedziółka-Jönsson, Jan Paczesny, Robert Hołyst
Fast and reliable bacteria detection is crucial for lowering the socioeconomic burden related to bacterial infections (e.g., in healthcare, industry or security). Bacteriophages (i.e., viruses with bacterial hosts) pose advantages such as great specificity, robustness, toughness and cheap preparation, making them popular biorecognition elements in biosensors and other assays for bacteria detection. There are several possible designs of bacteriophage-based biosensors. Here, we focus on developments based on whole virions as recognition agents. We divide the review into sections dealing with phage lysis as an analytical signal, phages as capturing elements in assays and phage-based sensing layers, putting the main focus on development reported within the past three years but without omitting the fundamentals.
Understanding missing proteins: a functional perspective Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-20 Longjian Zhou, Limsoon Wong, Wilson Wen Bin Goh
A missing protein (MP) is an unconfirmed genetic sequence for which a protein product is not yet detected. Currently, MPs are tiered based on supporting evidence mainly in the form of protein existence (PE) classification. As we discuss here, this definition is overly restrictive because proteins go missing in day-to-day proteomics as a result of low abundance, lack of sequence specificity, splice variants, and so on. Thus, we propose a broader functional classification of MPs that complements PE classification, discuss major causes, and examine three corresponding solution tiers:. biological, technical, and informatics. We assert that informatics-driven solutions would have a major role in resolving the MP problem (MPP).
Applications of stimuli-responsive nanoscale drug delivery systems in translational research Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-16 Mengjie Gu, Xin Wang, Tan Boon Toh, Edward Kai-Hua Chow
Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside.
Personalized nanomedicine for CNS diseases Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-15 Ajeet Kaushik, Rahul Dev Jayant, Vinay Bhardwaj, Madhavan Nair
Central nervous system (CNS) diseases are rapidly increasing globally. Currently used therapeutic agents to treat CNS diseases exhibit significant efficacy. However, the inability of these drugs to cross the blood–brain barrier (BBB) and invasiveness of the technologies to achieve localized drug delivery in disease-specific parts of the brain have thwarted pain-free and complete treatment of CNS diseases. Therefore, the safe, non-invasive, and targeted delivery of drugs to the brain using nanoparticles (NPs) is currently receiving considerable research attention. Here, we highlight advances in state-of-the-art personalized nanomedicine for the treatment of CNS diseases (with a focus on dementia), the related challenges, possible solutions, and prospects for nano-enabled personalized medicine.
The role of fMRI in drug development Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-15 Owen Carmichael, Adam J. Schwarz, Christopher H. Chatham, David Scott, Jessica A. Turner, Jaymin Upadhyay, Alexandre Coimbra, James A. Goodman, Richard Baumgartner, Brett A. English, John W. Apolzan, Preetham Shankapal, Keely R. Hawkins
Functional magnetic resonance imaging (fMRI) has been known for over a decade to have the potential to greatly enhance the process of developing novel therapeutic drugs for prevalent health conditions. However, the use of fMRI in drug development continues to be relatively limited because of a variety of technical, biological, and strategic barriers that continue to limit progress. Here, we briefly review the roles that fMRI can have in the drug development process and the requirements it must meet to be useful in this setting. We then provide an update on our current understanding of the strengths and limitations of fMRI as a tool for drug developers and recommend activities to enhance its utility.
Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-13 S.M. Moghimi
Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related ‘pseudoallergy’, where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered. However, the second hypothesis (the rapid phagocytic response hypothesis) states a transitional link from robust clearance of nanoparticles (NPs) from the blood by strategically placed responsive macrophages to adverse hemodynamic and cardiopulmonary reactions, regardless of complement activation. Here, I critically examine and discuss these hypotheses. Current experimentally derived evidence appears to be more in support of the rapid phagocytic response hypothesis than of the pseudoallergy hypothesis.
Galectin-3: mediator of microglia responses in injured brain Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-10 Reza Rahimian, Louis-Charles Béland, Jasna Kriz
Galectin-3 is a pleiotropic protein involved in cell activation, proliferation and migration and plays a pivotal part as an inflammatory mediator in neurodegeneration. Galectin-3 is associated with microglial activation and proliferation after ischemia. Given its putative role as a dynamic fine-tuner of microglia, activation of Galectin-3 provides molecular cues in design of new immunomodulatory strategies for stroke management. This review summarizes recent evidence on the role of Galectin-3 as a mediator of immune responses in damaged brain and mechanisms employed by Galectin-3 to affect microglial function.
Rare genetic diseases: update on diagnosis, treatment and online resources Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-10 Robert E. Pogue, Denise P. Cavalcanti, Shreya Shanker, Rosangela V. Andrade, Lana R. Aguiar, Juliana L.de Carvalho, Fabrício F. Costa
Rare genetic diseases collectively impact a significant portion of the world’s population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how a collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.
Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-10 Ashay Jain, Atul Jain, Prahlad Parajuli, Vijay Mishra, Gargi Ghoshal, Bhupinder Singh, Uma Shankar Shivhare, Om Prakash Katare, Prashant Kesharwani
Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand–receptor-mediated delivery of drug carriers.
Mesoporous silica nanoparticles: a smart nanosystem for management of breast cancer Drug. Discov. Today (IF 6.369) Pub Date : 2017-11-08 Neelam Poonia, Viney Lather, Deepti Pandita
Breast cancer is the second-leading cause of death in women worldwide owing to aggressive metastasis, lack of early diagnosis and poor access to treatment amenities. During the past decade, mesoporous silica nanoparticles (MSNs) have gained ground for the delivery of a wide variety of chemotherapeutic and bioimaging agents owing to their unique characteristics and straightforward fabrication methods. Present research studies based on MSNs have provided various potential insights in their applicability in breast cancer treatment by improving solubility and stability and decreasing the adverse effects of current treatment regimens. This review focuses on the applicability of this novel modality in the management of breast cancer.
What is precise pathophysiology in development of hypertension in pregnancy? Precision medicine requires precise physiology and pathophysiology Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-31 Qinqin Gao, Jiaqi Tang, Na Li, Bailin Liu, Mengshu Zhang, Miao Sun, Zhice Xu
It is widely accepted that placental ischemia is central in the evolution of hypertension in pregnancy. Many studies and reviews have targeted placental ischemia to explain mechanisms for initiating pregnancy hypertension. The placenta is rich in blood vessels, which are the basis for developing placental ischemia. However, is the physiology of placental vessels the same as that of nonplacental vessels? What is the pathophysiology of placental vessels in development of pregnancy hypertension? This review aims to provide a comprehensive summary of special features of placental vascular regulations and the pathophysiological changes linked to preeclamptic conditions. Interestingly, some popular theories or accepted concepts could be based on our limited knowledge and evidence regarding placental vascular physiology, pharmacology and pathophysiology. New views raised could offer interesting ideas for future investigation of mechanisms as well as targets for pregnancy hypertension.
Interfering peptides targeting protein–protein interactions: the next generation of drugs? Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-31 Heriberto Bruzzoni-Giovanelli, Valerie Alezra, Nicolas Wolff, Chang-Zhi Dong, Pierre Tuffery, Angelita Rebollo
Protein–protein interactions (PPIs) are well recognized as promising therapeutic targets. Consequently, interfering peptides (IPs) – natural or synthetic peptides capable of interfering with PPIs – are receiving increasing attention. Given their physicochemical characteristics, IPs seem better suited than small molecules to interfere with the large surfaces implicated in PPIs. Progress on peptide administration, stability, biodelivery and safety are also encouraging the interest in peptide drug development. The concept of an IP has been validated for several PPIs, generating great expectations for their therapeutic potential. Here, we describe approaches and methods useful for IP identification and in silico, physicochemical and biological-based strategies for their design and optimization. Selected promising in-vivo-validated examples are described and advantages, limitations and potential of IPs as therapeutic tools are discussed.
Fishing anti(lymph)angiogenic drugs with zebrafish Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-31 Melissa García-Caballero, Ana R. Quesada, Miguel A. Medina, Manuel Marí-Beffa
Zebrafish, an amenable small teleost fish with a complex mammal-like circulatory system, is being increasingly used for drug screening and toxicity studies. It combines the biological complexity of in vivo models with a higher-throughput screening capability compared with other available animal models. Externally growing, transparent embryos, displaying well-defined blood and lymphatic vessels, allow the inexpensive, rapid, and automatable evaluation of drug candidates that are able to inhibit neovascularisation. Here, we briefly review zebrafish as a model for the screening of anti(lymph)angiogenic drugs, with emphasis on the advantages and limitations of the different zebrafish-based in vivo assays.
NCp7: targeting a multitasking protein for next-generation anti-HIV drug development: covalent inhibitors Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-28 Luca Sancineto, Nunzio Iraci, Oriana Tabarrini, Claudio Santi
The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad-spectrum agents that are less prone to select for resistant strains. Here, we provide a comprehensive overview of the covalent NCp7 inhibitors that have emerged over the past 25 years of drug discovery campaigns, emphasising, where possible, their structure–activity relationships (SARs) and pharmacophoric features.
Current attempts to implement microRNA-based diagnostics and therapy in cardiovascular and metabolic disease: a promising future Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-28 Punniyakoti V. Thanikachalam, Srinivasan Ramamurthy, Zheng W. Wong, Koo B. Jin, Wong J. Ying, Mohd F.B. Abdullah, Chin Y. Haur, Chia C. Hou, Tan J. Yi, Neo W. Ting, Tan B. Sen, Khan W. Fang, Prashant Kesharwani
MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression at the post-translational level. miRNA-based therapeutic agents are important because of the functionality of miRNAs in regulating lipid and glucose metabolism and their role in the pathogenesis of metabolic disorders such as diabetes and obesity, where dysregulation leads to disease; they are also important in angiogenesis. miRNAs additionally serve as biomarkers in the diagnosis, prognosis and risk assessment of disease and in monitoring the response to treatment. Here, we provide a brief overview of progress in miRNA-based therapeutics in the preclinical and clinical setting and highlight the novel outcomes and opportunities in the diagnosis and treatment of metabolic conditions. In addition, we present the role of miRNAs in stem cell therapy which could have great potential in regenerative medicine.
Alternative fluorophores designed for advanced molecular imaging Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-27 Lara G. Freidus, Priyamvada Pradeep, Pradeep Kumar, Yahya E. Choonara, Viness Pillay
Anticancer activity of seaweeds Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-26 Anllely G. Gutiérrez-Rodríguez, Claudia Juárez-Portilla, Tatiana Olivares-Bañuelos, Rossana C. Zepeda
Cancer is a major health problem worldwide and still lacks fully effective treatments. Therefore, alternative therapies, using natural products, have been proposed. Marine algae are an important component of the marine environment, with high biodiversity, and contain a huge number of functional compounds, including terpenes, polyphenols, phlorotannins, and polysaccharides, among others. These compounds have complex structures that have shown several biological activities, including anticancer activity, in several in vitro and in vivo models. Moreover, seaweed-derived compounds target important molecules that regulate cancer processes. Here, we review our current understanding of the anticancer activity of seaweeds.
Indacaterol/glycopyrronium: a dual bronchodilator for COPD Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-24 Donald Banerji, Robert Fogel, Francesco Patalano
Indacaterol/glycopyrronium (IND/GLY) 110/50 mg was the first once-daily, long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). Development of IND/GLY was driven by the need to improve the standard of care for patients with this disease, in terms of symptom control and exacerbation frequency. IGNITE, an adaptive, comprehensive, and innovative Phase 3 development program, demonstrated the efficacy of IND/glycopyrronium in optimising bronchodilation, reducing symptoms, and reducing exacerbations in patients with COPD. IGNITE challenged contemporary thinking about the pharmacological treatment and management of patients with this disease.
3D nerve cell cultures and complex physiological relevance Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-23 Xin Cheng, Kenneth Ndyabawe, Amish Asthana, William S. Kisaalita
The field of tissue engineering has not yet provided knowledge on which a consensus for the complex physiological relevance (CPR) of neuronal cultures could be established. The CPR of 3D neuronal cultures can have a profound impact on the drug discovery process through the validation of in vitro models for the study of neuropsychiatric and degenerative diseases, as well as screening for neurotoxicity during drug development. Herein, we assemble evidence in support of the potential of [Ca2+]i oscillation frequency as a CPR outcome that can demonstrate the in vivo-like behavior of 3D cultures and differentiate them from 2D monolayers. We demonstrate that [Ca2+]i oscillation frequencies in 2D cultures are significantly higher than those found in 3D cultures, and provide a possible molecular explanation.
Gemcitabine and glioblastoma: challenges and current perspectives Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-23 Chiara Bastiancich, Guillaume Bastiat, Frederic Lagarce
Gemcitabine is a nucleoside analog currently used for the treatment of various solid tumors as a single agent or in combination with other chemotherapeutic drugs. Its use against highly aggressive brain tumors (glioblastoma) has been evaluated in preclinical and clinical trials leading to controversial results. Gemcitabine can inhibit DNA chain elongation, is a potent radiosensitizer and it can enhance antitumor immune activity, but it also presents some drawbacks (e.g., short half-life, side effects, chemoresistance). The aim of this review is to discuss the challenges related to the use of gemcitabine for glioblastoma and to report recent studies that suggest overcoming these obstacles opening new perspectives for its use in the field (e.g., gemcitabine derivatives and/or nanomedicines).
Microarray patches: potentially useful delivery systems for long-acting nanosuspensions Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-23 Ryan F. Donnelly, Eneko Larrañeta
Long-acting drug nanosuspension formulations are coming to the fore as controlled release strategies for several medical conditions and as a preventative measure against HIV infection. However, such delivery systems must, by necessity, be given by hypodermic injection, typically into muscle. This poses problems for patients who are needle-phobic, given that injections have to be administered on a weekly or monthly basis. Needle-stick injuries, inappropriate reuse of needles, and poor disposal practices are major challenges in developing countries. Dissolving microneedles (MNs) are capable of delivering high drug doses, if suitably designed and formulated, and are also capable of delivering nanoparticles (NPs) into viable skin. Given that such microneedles are minimally invasive and self-disabling, the potential for major enhancement in patient care and compliance exists. In this review, we explore the key considerations in the development of these combination drug delivery systems.
Marketing authorisation of orphan medicines in Europe from 2000 to 2013 Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-23 Matthias P. Hofer, Hanna Hedman, Maria Mavris, Franz Koenig, Thorsten Vetter, Martin Posch, Spiros Vamvakas, Jan Regnstrom, Stiina Aarum
An analysis was performed on a data set of 157 orphan designated medicines with an outcome for marketing authorisation application (MAA) between 2000 and 2013. The intention was to understand the factors associated with marketing authorisation success, the challenges developers face regarding orphan medicine development, and how scientific advice (SA) is used during development. The results demonstrated that orphan medicines have a lower success rate compared with non-orphan medicines and that determinants for marketing authorisation success were company size and compliance with SA. Compliance with SA could help orphan medicine developers overcome clinical development challenges.
Computational drug repositioning for rare diseases in the era of precision medicine Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-18 Brian Delavan, Ruth Roberts, Ruili Huang, Wenjun Bao, Weida Tong, Zhichao Liu
There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.
Biochemical marker discovery, testing and evaluation for facilitating OA drug discovery and development Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-14 Anne-Christine Bay-Jensen, Christian S. Thudium, Oreste Gualillo, Ali Mobasheri
Insights from pharmacological similarity of epigenetic targets in epipolypharmacology Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-14 J.Jesús Naveja, José L. Medina-Franco
Haspin: a promising target for the design of inhibitors as potent anticancer drugs Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-13 Nathalie Gisèle Amoussou, André Bigot, Christos Roussakis, Jean-Michel H. Robert
Protein kinases constitute a large group of enzymes in eukaryotes and have an important role in many cellular processes. Several of these proteins are active kinases, such as haploid germ cell-specific nuclear protein kinase (Haspin), an atypical eukaryotic protein kinase that lacks sequence similarity with other eukaryotic protein kinases. Haspin is a serine/threonine kinase that associates with chromosome and phosphorylates threonine 3 of histone 3 during mitosis. Haspin overexpression or deletion results in defective mitosis. It has been shown that Haspin inhibitors have potent anti-tumoral effects. Given that the only Haspin substrate is threonine 3 of histone 3, inhibition of Haspin might have fewer adverse effects compared with XXXX. Here, we highlight the chemical structures and actions of currently known Haspin inhibitors.
Molecular dynamics simulation strategies for designing carbon-nanotube-based targeted drug delivery Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-13 Mohammed N. Al-Qattan, Pran K. Deb, Rakesh K. Tekade
Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-13 Francesco Cilurzo, Umberto M. Musazzi, Silvia Franzé, Francesca Selmin, Paola Minghetti
Orodispersible dosage forms have a growing presence in the pharmaceutical market because their administration can improve the bioavailability of some drugs and their prescription can ameliorate patient adherence and/or compliance. Here, we review the main features of orodispersible tablets, including oral lyophilisates, and orodispersible films along with their main production technologies. We summarize the bioavailability data and critically discussed their potential to improve patient adherence and/or compliance. We revisit this information in light of both the European Union (EU) and US regulatory frameworks, focusing on the differences in the definitions of such dosage forms and the requirements for marketing authorization.
Medicinal chemistry in drug discovery in big pharma: past, present and future Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-12 Ian B. Campbell, Simon J.F. Macdonald, Panayiotis A. Procopiou
The changes in synthetic and medicinal chemistry and related drug discovery science as practiced in big pharma over the past few decades are described. These have been predominantly driven by wider changes in society namely the computer, internet and globalisation. Thoughts about the future of medicinal chemistry are also discussed including sharing the risks and costs of drug discovery and the future of outsourcing. The continuing impact of access to substantial computing power and big data, the use of algorithms in data analysis and drug design are also presented. The next generation of medicinal chemists will communicate in ways that reflect social media and the results of constantly being connected to each other and data.
Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-12 Mahaveer Singh, Hemant R. Jadhav
Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790 M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790 M mutants, sparing wild-type EGFR. EGFR TKIs have fewer adverse effects than chemotherapy and also improve progression-free survival. Combination therapy of EGFR TKIs with anti-EGFR antibodies is recommended for overcoming the problem of resistance to some extent. This review could help medicinal chemists to design novel EGFR TKIs against NSCLC.
Discovery of hidden allosteric sites as novel targets for allosteric drug design Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-10 Shaoyong Lu, Mingfei Ji, Duan Ni, Jian Zhang
Hidden allosteric sites, as a novel type of allosteric site, are invisible in ligand-unbound (apo) crystal structures, but can emerge in ligand-bound (holo) crystal structures when a specific ligand binds to, and stabilizes, a unique conformation favored by the ligand. However, the identification of these sites is a significant challenge. Several computational and experimental approaches have been developed to identify such sites in proteins. Here, we outline these approaches, with a focus on examples of the successful use of such techniques. The discovery of hidden allosteric sites offers a new avenue for facilitating drug design by greatly expanding the repertoire of available drug targets, contributing to the search for allosteric drugs for the treatment of human diseases.
Demonstrating significant benefit of orphan medicines: analysis of 15 years of experience in Europe Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-09 Laura Fregonese, Lesley Greene, M. Hofer, Armando Magrelli, Frauke Naumann-Winter, Kristina Larsson, Maria Sheean, Violeta Stoyanova-Beninska, Stelios Tsigkos, Kerstin Westermark, Bruno Sepodes
In the European Union demonstration of ‘significant benefit’ is mandatory if satisfactory methods exist for a disease targeted by a new orphan medicinal product. Significant benefit is required at the time of orphan designation, when it can be supported by preclinical studies, and at the time of marketing authorization, when clinical data are needed. For the first time, our work has identified, defined and organized the scientific grounds on which significant benefit is granted in the European Union, based on a review of the orphan medicinal products authorized in the years 2000–2015, and on the working experience of the Committee of Orphan Medicinal Products. The resulting conceptual framework is a tool for medicine developers to reflect on potential areas of advantage of their candidate products, and for a broad range of stakeholders to stimulate the discussion on the added value of orphan medicines across the whole development lifecycle.TeaserAn analysis of the scientific grounds of the ‘significant benefit’ as per the European Regulation, supporting the added value for patients of those orphan medicinal products that demonstrate to be of significant benefit.
Phenytoin repositioned in wound healing: clinical experience spanning 60 years Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-06 Jan M. Keppel Hesselink
Drug repositioning is hot, and much development time and money can be spared if one selects an old drug and explores the efficacy and safety in a new indication. Phenytoin is studied and repositioned in many disorders after the initial indication epilepsy (from 1937). Its repositioning in depression was put in the spotlight by the Wall Street icon Jack Dreyfus, already in the 1970s. Innovations in the field of phenytoin still appear to be possible for a number of indications such as wound healing, bipolar disorder and aggression, and via a topical formulation for neuropathic pain. We will discuss wound healing and identified a number of critical issues related to its repositioning in this indication.
Locked nucleic acid: modality, diversity, and drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-06 Peter H. Hagedorn, Robert Persson, Erik D. Funder, Nanna Albæk, Sanna L. Diemer, Dennis J. Hansen, Marianne R. Møller, Natalia Papargyri, Helle Christiansen, Bo R. Hansen, Henrik F. Hansen, Mads A. Jensen, Troels Koch
Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide compound is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.
Relict plastidic metabolic process as a potential therapeutic target Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-05 Drista Sharma, Rani Soni, Praveen Rai, Bhaskar Sharma, Tarun Kumar Bhatt
The alignment of the evolutionary history of parasites with that of plants provides a different panorama in the drug development process. The housing of different metabolic processes, essential for parasite survival, adds to the indispensability of the apicoplast. The different pathways responsible for fueling the apicoplast and parasite offer a myriad of proteins responsible for the apicoplast function. The studies emphasizing the target-based approaches might help in the discovery of antimalarials. The different putative drug targets and their roles are highlighted. In addition, the origin of the apicoplast and metabolic processes are reviewed and the different drugs acting upon the enzymes of the apicoplast are discussed.
Overcoming or circumventing the stratum corneum barrier for efficient transcutaneous immunization Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-05 Zhongjian Chen, Yongjiu Lu, Jianping Qi, Quangang Zhu, Yi Lu, Wei Wu
Transcutaneous immunization (TCI) is a promising alternative to vaccine delivery via the subcutaneous and intramuscular routes because of the unique immunological characteristics of the skin. However, the stratum corneum (SC) prevents entry of most therapeutic compounds into the body. Several physical devices have been developed to overcome the SC barrier, but still damage the skin. However, by targeting antigens to the abundant perifollicular antigen-presenting cells (APCs), the transfollicular route might be a promising approach for TCI without compromising the skin barrier.
Patient-centered clinical trials for medical devices Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-04 Shomesh E. Chaudhuri, Martin P. Ho, Telba Irony, Murray Sheldon, Andrew W. Lo
We apply Bayesian decision analysis to incorporate patient preferences in the regulatory approval process for new therapies. By assigning weights to type I and type II errors based on patient preferences, the significance level (α) and power (1 − β) of a randomized clinical trial (RCT) for a new therapy can be optimized to maximize the value to current and future patients and, consequently, to public health. We find that, for weight-loss devices, potentially effective, low-risk treatments have optimal αs larger than the traditional one-sided significance level of 5%, whereas potentially less effective and riskier treatments have optimal αs below 5%. Moreover, the optimal RCT design, including trial size, varies with the risk aversion and time-to-access preferences as well as the medical need of the target population.
Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-04 Maria E. Sheean, Violeta Stoyanova-Beninska, Giuseppe Capovilla, Dinah Duarte, Matthias P. Hofer, Michel Hoffmann, Armado Magrelli, Segundo Mariz, Stelios Tsigkos, Evyenia Shaili, Benedetta Polsinelli, Mario Ricciardi, Milton Bonelli, Pavel Balabanov, Kristina Larsson, Bruno Sepodes
Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient.
HDL functionality in familial hypercholesterolemia: effects of treatment modalities and pharmacological interventions Drug. Discov. Today (IF 6.369) Pub Date : 2017-10-03 Shiva Ganjali, Amir Abbas Momtazi, Maciej Banach, Petri T. Kovanen, Antonio M. Gotto Jr, Amirhossein Sahebkar
Recent studies have demonstrated that assessment of high-density lipoprotein (HDL) functionality indices, instead of HDL cholesterol measurement, is a more robust tool for the evaluation of the functional status of HDL and cardiovascular risk. There are qualitative abnormalities of HDL particles in familial hypercholesterolemia (FH) patients that might represent potential therapeutic targets. Despite the potential promise of optimizing HDL functionality for the treatment of FH, there has been no prior comprehensive review focusing on the impact of different lipid-modifying therapies on HDL functionality in FH patients. In the present review, we aim to fulfill this gap and provide a concise summary on the impact of different lipid-modifying therapies on HDL functionality in FH.
Carbon nanomaterials in oncology: an expanding horizon Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-28 Neelesh K. Mehra, Amit K. Jain, Manoj Nahar
Carbon nanomaterials have been attracting attention in oncology for the development of safe and effective cancer nanomedicines in increasing improved patient compliance for generally recognized as safe (GRAS) prominence. Toxicity, safety and efficacy of carbon nanomaterials are the major concerns in cancer theranostics. Various parameters such as particle size and shape or surface morphology, surface charge, composition, oxidation and nonoxidative-stress-related mechanisms are prone to toxicity of the carbon nanomaterials. Currently, few cancer-related products have been available on the market, although some are underway in preclinical and clinical phases. Thus, our main aim is to provide comprehensive details on the carbon nanomaterials in oncology from the past two decades for patient compliance and safety.
Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-22 Mahalakshmi Ramadoss, Vijayalakshmi Mahadevan
Epigenetic and genomic alterations regulate the transcriptional landscape of cells during cancer onset and progression. Recent clinical studies targeting the epigenetic ‘readers’ (bromodomains) for cancer therapy have established the effectiveness of bromodomain (BRD) extraterminal (BET) inhibitors in treating several types of cancer. In this review, we discuss key mechanisms of BET inhibition and synergistic combinations of BET inhibitors with histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), kinase, B-cell lymphoma 2 (Bcl-2) and proteosome inhibitors, and immunomodulatory drugs for cancer therapy. We also highlight the potential of such combinations to overcome drug resistance, and the evolving approaches to developing novel BET inhibitors.
European regulatory use and impact of subgroup evaluation in marketing authorisation applications Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-21 Julien Tanniou, Steven Teerenstra, Sagal Hassan, Andre Elferink, Ingeborg van der Tweel, Christine Gispen-de Wied, Kit C.B. Roes
Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012–2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication.
Guiding principles of value creation through collaborative innovation in pharmaceutical research Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-20 Liang Schweizer, Jeff He
Open innovation has become the main trend in pharmaceutical research. Potential obstacles and pitfalls of collaborations often lead to missed opportunities and/or poorly executed partnerships. This paper aims to provide a framework that facilitates the execution of successful collaborations. We start by mapping out three checkpoints onto early-stage collaborative partnerships: inception, ignition and implementation. Different value types and value drivers are then laid out for each stage of the partnership. We proceed to propose a ratio-driven approach and a value-adjustment mechanism, enhancing the probability of successes in pharmaceutical research collaborations. These guiding principles combined should help the partners either reach agreement more quickly or move on to the next potential project.
Market entry, power, pharmacokinetics: what makes a successful drug innovation? Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-20 Susanne Alt, Axel Helmstädter
Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we use historical market data relating to pharmacokinetic (PK), pharmacodynamic (PD), and other drug-related properties to investigate which derivatives within certain drug classes have been most successful on the market. Based on our investigations, we suggest naming the most successful drugs ‘overtaking innovation’, because they often exceed the market share of all the other derivatives combined. Seven drug classes showed that the overtaking innovation is never a radical innovation, but rather an early incremental innovation, with advantages in manageability and/or tolerance.
Strategies for the enhanced intracellular delivery of nanomaterials Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-15 Cláudia Azevedo, Maria Helena Macedo, Bruno Sarmento
The intracellular delivery of nanomaterials and drugs has been attracting increasing research interest, mainly because of their important effects and functions in several organelles. Targeting specific organelles can help treat or decrease the symptoms of diabetes, cancer, infectious, and autoimmune diseases. Tuning biological and chemical properties enables the creation of functionalized nanomaterials with enhanced intracellular uptake, ability to escape premature lysosome degradation, and to reach a specific target. Here, we provide an update of recent advances in the intracellular delivery mechanisms that could help drugs reach their target more efficiently.
Uncovering novel repositioning opportunities using the Open Targets platform Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14 Mugdha Khaladkar, Gautier Koscielny, Samiul Hasan, Pankaj Agarwal, Ian Dunham, Deepak Rajpal, Philippe Sanseau
The recently developed Open Targets platform consolidates a wide range of comprehensive evidence associating known and potential drug targets with human diseases. We have harnessed the integrated data from this platform for novel drug repositioning opportunities. Our computational workflow systematically mines data from various evidence categories and presents potential repositioning opportunities for drugs that are marketed or being investigated in ongoing human clinical trials, based on evidence strength on target–disease pairing. We classified these novel target–disease opportunities in several ways: (i) number of independent counts of evidence; (ii) broad therapy area of origin; and (iii) repositioning within or across therapy areas. Finally, we elaborate on one example that was identified by this approach.
Molecular targets and pathways for the treatment of visceral leishmaniasis Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14 Vineet Jain, Keerti Jain
Visceral leishmaniasis (VL) represents the most severe form of the tropical disease, leishmaniasis. Treatment of VL is complicated because of the few clinically approved antileishmanial drugs available; emerging resistance to first-line drugs; need for a temperature-controlled ‘cold’ supply chain; serious toxicity concerns over drugs such as Amphotericin B; high cost of medication; and unavailability of clinically approved antileishmanial vaccines. Attacking potential molecular targets, specific to the parasite, is a vital step in the treatment of this and other infectious diseases. As we discuss here, comprehensive investigation of these targets could provide a promising strategy for the treatment of visceral leishmaniasis.
CHEMGENIE: integration of chemogenomics data for applications in chemical biology Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14 Peter S. Kutchukian, Charlie Chang, Sean J. Fox, Erica Cook, Richard Barnard, David Tellers, Huijun Wang, Dante Pertusi, Meir Glick, Robert P. Sheridan, Iain Wallace, Anne Mai Wassermann
Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data do not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness their potential. Here, we describe ongoing efforts at Merck & Co. to structure data in the area of chemogenomics. We are integrating complementary data from both internal and external data sources into one chemogenomics database (Chemical Genetic Interaction Enterprise; CHEMGENIE). Here, we demonstrate how this well-curated database facilitates compound set design, tool compound selection, target deconvolution in phenotypic screening, and predictive model building.
Circulatory-cell-mediated nanotherapeutic approaches in disease targeting Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-14 Thierry Burnouf, Pierre-Alain Burnouf, Yu-Wen Wu, Er-Yuan Chuang, Long-Sheng Lu, Hadi Goubran
Circulating blood cells, and cell-derived microvesicles, are emerging as pragmatic delivery systems that can smartly complement the already existing nanotherapeutic platforms evaluated to treat or diagnose diseases. The valuable distinctive features of circulatory cells over synthetic nanocarriers encompass their biological origin which confers immune transparence, known biodegradability, high drug loading, relatively long half-life and a targeting capacity associated with their physiological surface functionality. Absence of nuclei in red blood cells and platelets provides further rationale for their use as cargo vehicles for nucleotoxic agents. Ongoing developments in cell-based and cell-inspired nanotherapies can move drug delivery into reachable frontiers and exhibit high potentiality for translatability into clinical use.
High-throughput flow cytometry for drug discovery: principles, applications, and case studies Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-12 Mei Ding, Karin Kaspersson, David Murray, Catherine Bardelle
Flow cytometry is a technology providing multiparametric analysis of single cells or other suspension particles. High-throughput (HT) flow cytometry has become an attractive screening platform for drug discovery. In this review, we highlight the recent HT flow cytometry applications, and then focus on HT flow cytometry deployment at AstraZeneca (AZ). Practical considerations for successful HT flow cytometry assay development and screening are provided based on experience from four project case studies at AZ. We provide an overview of the scientific rationale, explain why HT flow cytometry was chosen and how HT flow cytometry assays deliver new ways to support the drug discovery process.
Near infrared spectroscopy: a tool for solid-state characterization Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-08 Rahul B. Chavan, Nallamothu Bhargavi, Anurag Lodagekar, Nalini R. Shastri
Revisiting asthma therapeutics: focus on WNT signal transduction Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-07 Tim Koopmans, Reinoud Gosens
Asthma is a complex disease of the airways that develops as a consequence of both genetic and environmental factors. This interaction has highlighted genes important in early life, particularly those that control lung development, such as the Wingless/Integrase-1 (WNT) signalling pathway. Although aberrant WNT signalling is involved with an array of human conditions, it has received little attention within the context of asthma. Yet it is highly relevant, driving events involved with inflammation, airway remodelling, and airway hyper-responsiveness (AHR). In this review, we revisit asthma therapeutics by examining whether WNT signalling is a valid therapeutic target for asthma.
Towards carborane-functionalised structures for the treatment of brain cancer Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-05 Gianpiero Calabrese, Anis Daou, Eugen Barbu, John Tsibouklis
Boron neutron capture therapy (BNCT) is a promising targeted chemoradiotherapeutic technique for the management of invasive brain tumors, such as glioblastoma multiforme (GBM). A prerequisite for effective BNCT is the selective targeting of tumour cells with 10B-rich therapeutic moieties. To this end, polyhedral boranes, especially carboranes, have received considerable attention because they combine a high boron content with relative low toxicity and metabolic inertness. Here, we review progress in the molecular design of recently investigated carborane derivatives in light of the widely accepted performance requirements for effective BNCT.
From machine learning to deep learning: progress in machine intelligence for rational drug discovery Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-04 Lu Zhang, Jianjun Tan, Dan Han, Hao Zhu
Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure–activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply. However, when drug discovery moved into the era of ‘big’ data, machine learning approaches evolved into deep learning approaches, which are a more powerful and efficient way to deal with the massive amounts of data generated from modern drug discovery approaches. Here, we summarize the history of machine learning and provide insight into recently developed deep learning approaches and their applications in rational drug discovery. We suggest that this evolution of machine intelligence now provides a guide for early-stage drug design and discovery in the current big data era.
Finding hidden treasures in old drugs: the challenges and importance of licensing generics Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-01 Melek Simsek, Berrie Meijer, Adriaan A. van Bodegraven, Nanne K.H. de Boer, Chris J.J. Mulder
Identifying new indications for existing drugs creates new therapeutic options while bypassing much of the costs and time involved with bringing a new drug to market. The rediscovery of a generic drug, however, is a challenging pursuit because there is no formal regulatory approach and a lack of economic interest by pharmaceutical companies. This played a part in the re-registration of thioguanine as a rescue drug for the treatment of patients with inflammatory bowel disease in The Netherlands. In this article, we aim to underline the importance of drug rediscovery, the difficulties of this procedure in Europe and we attempt to suggest conceivable solutions.
Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering Drug. Discov. Today (IF 6.369) Pub Date : 2017-09-01 Hong Zhao, Ruihua Ding, Xin Zhao, Yiwei Li, Liangliang Qu, Hao Pei, Lara Yildirimer, Zhengwei Wu, Weixia Zhang
Here, we discuss the biomedical applications of graphene-based nanomaterials (GBNs). We examine graphene and its various derivatives, including graphene, graphene oxides (GOs), reduced graphene oxides (rGOs), graphene quantum dots (GQDs), and graphene composites, and discuss their unique properties related to their biomedical applications. We also summarize the detailed biomedical applications of GBNs, including drug and/or gene delivery, bioimaging, and tissue engineering. We also highlight the toxicity of these nanomaterials.
RanBPM: a potential therapeutic target for modulating diverse physiological disorders Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-26 Soumyadip Das, Bharathi Suresh, Hyongbum (Henry) Kim, Suresh Ramakrishna
The Ran-binding protein microtubule-organizing center (RanBPM) is a highly conserved nucleocytoplasmic protein involved in a variety of intracellular signaling pathways that control diverse cellular functions. RanBPM interacts with proteins that are linked to various diseases, including Alzheimer’s disease (AD), schizophrenia (SCZ), and cancer. In this article, we define the characteristics of the scaffolding protein RanBPM and focus on its interaction partners in diverse physiological disorders, such as neurological diseases, fertility disorders, and cancer.
Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca–Charles-River-Laboratories strategic relationship Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-26 Frederic D.C. Martin, Amanda Benjamin, Ruth MacLean, David M. Hollinshead, Claire Landqvist
In 2012, AstraZeneca entered into a strategic relationship with Charles Rivers Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies.
Zinc oxide nanoparticles: a promising nanomaterial for biomedical applications Drug. Discov. Today (IF 6.369) Pub Date : 2017-08-25 Pawan K. Mishra, Harshita Mishra, Adam Ekielski, Sushama Talegaonkar, Bhuvaneshwar Vaidya
Zinc oxide (ZnO) nanoparticles (NPs) are a promising platform for use in biomedical research, especially given their anticancer and antimicrobial activities. These activities are associated with the ability of ZnO NPs to generate reactive oxygen species (ROS) and induce apoptosis. In addition, ZnO NPs have been successfully exploited as drug carriers for loading and transporting drugs to target sites, thereby reducing unwanted toxicity and off-target effects, and resulting in amplified synergistic effects. Here, we discuss the synthesis and biomedical applications of ZnO NPs.Teaser: Zinc oxide nanoparticles: how useful will they be in the biomedical sciences?
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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