Nature Reviews Drug Discovery contents November 2016 Volume 15 Number 11 pp 731-769

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TABLE OF CONTENTS
November 2016 Volume 15 Number 11		Advertisement
2015 2-year Impact Factor 47.120 Journal Metrics 2-year Median 31	In this issue Comment News and Analysis Research Highlights Perspectives Reviews Also this month Article series: A guide to drug discovery  Featured article: Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design Jonathan M. L. Ostrem and Kevan M. Shokat	Collaboration Yields a Potential New Therapy for Usher Syndrome Usher III Initiative Research Consortium scientists have detailed an approach that enabled them to identify and characterize a novel small molecule against hearing loss associated with this disorder. Their findings may have farther reaching applications. Read the article in Nature Chemical Biology (free).
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Comment: Patients as key partners in rare disease drug development Max G. Bronstein & Emil D. Kakkis p731 | doi:10.1038/nrd.2016.133 Rare disease drug development could benefit substantially from increased patient engagement and input to enhance understanding of the key aspects of disease impact, ways to measure these impacts and patients' perspectives on the benefit-risk profile of potential therapies. Abstract | Full Text | PDF | Supplementary information
NEWS AND ANALYSIS		Top
First hearing-disorder drugs stumble Katie Kingwell p733 | doi:10.1038/nrd.2016.222 Clinical trial failures of two drugs for hearing loss and tinnitus underscore pitfalls for a nascent area of drug development, but lessons learned may help in navigating the uncharted path to approval. PDF
Cancer metabolism pipeline breaks new ground Asher Mullard p735 | doi:10.1038/nrd.2016.223 Although Agios and Celgene are set to file for approval for their first-in-class cancer metabolism drug, the field has started looking in new directions for the next batch of metabolic targets. PDF
NEWS IN BRIEF Symptomatic AD treatment fails in first phase III Asher Mullard p738 | doi:10.1038/nrd.2016.225 PDF
NEWS IN BRIEF RNAi hits another rut Asher Mullard p738 | doi:10.1038/nrd.2016.226 PDF
NEWS IN BRIEF Immuno-oncology drugs jostle for first-line setting Asher Mullard p738 | doi:10.1038/nrd.2016.227 PDF
BIOBUSINESS BRIEFS Regulatory watch: Innovative drug availability in China Liming Shao, Lili Xu, Qiu Li, Ranjana Chakravarthy, Ziling Yang & Kenneth I Kaitin p739 | doi:10.1038/nrd.2016.200 PDF
BIOBUSINESS BRIEFS Patent watch: Microscale implantable drug delivery systems: emerging IP strategies Dana Daukss & Kennyn Statler p740 | doi:10.1038/nrd.2016.210 PDF
AN AUDIENCE WITH Deborah Zarin p742 | doi:10.1038/nrd.2016.215 Deborah Zarin, director of ClinicalTrials.gov, discusses the new trial registration rules and the need for transparency in the clinical research enterprise. PDF
FROM THE ANALYST'S COUCH Nonalcoholic steatohepatitis (NASH) drugs market Sorcha Cassidy & Basharut A. Syed p745 | doi:10.1038/nrd.2016.188 Nonalcoholic steatohepatitis (NASH), an extreme form of nonalcholic fatty liver disease, is predicted to become the leading reason for liver transplantation by 2020. This analysis provides an overview of emerging therapies for NASH. PDF
RESEARCH HIGHLIGHTS Top Cancer: Closing the door on KRAS-mutant lung cancer p747 | doi:10.1038/nrd.2016.216 PDF Hypertension: Purinergic receptor inhibition lowers blood pressure p748 | doi:10.1038/nrd.2016.217 PDF HIV: Sequential vaccine elicits broadly neutralizing antibodies p748 | doi:10.1038/nrd.2016.228 PDF Anticancer drugs: Translating the undruggable target p749 | doi:10.1038/nrd.2016.214 PDF Antimicrobial drugs: Multifaceted approach to multidrug resistance p750 | doi:10.1038/nrd.2016.224 PDF IN BRIEF Malaria: Novel antimalarial target identified | Anticancer agents: ACC inhibition suppresses lung cancer | Lysosomal storage diseases: HSP70 reverses lysosomal pathology | Autoimmune disease: CK2 blockade ameliorates EAE PDF
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REVIEWS		Top
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design Jonathan M. L. Ostrem & Kevan M. Shokat p771 | doi:10.1038/nrd.2016.139 KRAS is one of the most frequently activated proteins in cancer, yet the development of RAS inhibitors has proven to be extremely challenging. Here, Shokat and Ostrem discuss the latest insights into RAS structure and dynamics, consider potential mechanisms of action for effective RAS inhibitors, and examine recent reports of direct RAS inhibitors. Abstract | Full Text | PDF | Supplementary information
Targeting hepatic glucose metabolism in the treatment of type 2 diabetes Amy K. Rines, Kfir Sharabi, Clint D. J. Tavares & Pere Puigserver p786 | doi:10.1038/nrd.2016.151 Although the liver has a key role in maintaining blood glucose homeostasis, few existing type 2 diabetes therapies directly target this organ. Here, Puigserver et al. provide an overview of the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, focusing on emerging strategies to target hepatic glucose metabolism for the treatment of diabetes. Abstract | Full Text | PDF
PERSPECTIVES		Top
OPINION Article series: A guide to drug discovery Screening out irrelevant cell-based models of disease Peter Horvath, Nathalie Aulner, Marc Bickle, Anthony M. Davies, Elaine Del Nery, Daniel Ebner, Maria C. Montoya, Päivi Östling, Vilja Pietiäinen, Leo S. Price, Spencer L. Shorte, Gerardo Turcatti, Carina von Schantz & Neil O. Carragher p751 | doi:10.1038/nrd.2016.175 Traditional cell-based disease models often fail to adequately represent key disease characteristics, increasing the risk of subsequent attrition in clinical trials. This article presents a set of principles for disease-relevant assays, and discusses new opportunities for exploiting advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells as well as 3D co-culture and organ-on-a-chip systems, which are being complemented by progress with single-cell imaging and gene editing technologies. Abstract | Full Text | PDF
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