Drug Discovery@nature.com 7 June 2013

TABLE OF CONTENTS 7 June 2013 News Analysis Research Highlights Research & Reviews Careers Nature Reviews Drug Discovery is on Twitter Advertisement SciBX: Science Business eXchange Innovation in Drug Discovery Challenge: Harnessing Endocytosis for Drug Discovery SciBX, in partnership with Innocentive, is requesting ideas from the scientific community to progress the understanding of how large therapeutic molecules can effectively intercept and use the endocytosis process to achieve class-wide cell permeability. Click here to find out more!   News Top All-oral HCV therapies near approval doi:10.1038/nrd4036 Gilead has filed the first interferon-free hepatitis C virus regimen for approval in the United States, but drug developers are making strides with better combinations. Full Text Integrin inhibitors go with the gut doi:10.1038/nrd4037 Takeda has filed for European approval of vedolizumab in inflammatory bowel disease, potentially providing new hope for spurned integrin inhibitors. Full Text Regulatory watch: Enhanced chance of success for protein replacement therapies doi:10.1038/nrd4027 Protein replacement therapies for rare monogenic diseases have a higher success rate for approval than biologics, small molecules and orphan drugs in general, according to a recently published report. Full Text Trial watch: Opioid receptor blocker shows promise in Phase II depression trial doi:10.1038/nrd4028 Results from a Phase II trial of Alkermes's ALKS 5461, a therapeutic that acts as a κ-opioid receptor antagonist, indicate that it improves symptoms in patients with major depressive disorder who do not respond to current therapies. Full Text Analysis Top What matters most in commercial success: first-in-class or best-in-class? doi:10.1038/nrd4035 Given that it is common for several companies to be simultaneously pursuing promising new targets, this analysis investigates the question of whether it is better to be first or best in a particular new class of drugs. Full Text RON's new role doi:10.1038/scibx.2013.507 A team has shown that inhibiting the kinase RON could fight cancer metastasis by stimulating an antitumour immune response, building a case for focusing drug discovery efforts specifically against RON, which has long been neglected in favour of its relative, MET. Full Text Research Highlights Top Inflammatory disorders: Targeting TRAFs tames inflammation doi:10.1038/nrd4029 Inhibition of tumour necrosis factor receptor-associated factors (TRAFs) through FBX03 could represent a novel potential anti-inflammatory therapeutic strategy. Full Text G protein-coupled receptors: Pioneering Frizzled family receptor structure solved doi:10.1038/nrd4030 A crystal structure of the human Smoothened (SMO) receptor — an essential component of the Hedgehog signalling pathway — bound to an antitumour compound has been solved. Full Text Analgesia: A new player in neuropathic pain pathogenesis doi:10.1038/nrd4031 The WNT family of proteins, which are involved in the regulation of cellular processes during nervous system development, have a key role in the pathogenesis of neuropathic pain. Full Text Research & Reviews Top Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases doi:10.1038/nrd4010 Although nucleoside analogues have been used clinically for decades, efforts continue to improve response rates and reduce side effects. This article highlights recent progress in the development of new nucleoside and nucleotide analogues for cancer and viral diseases. Full Text The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer doi:10.1038/nrc3521 This article discusses deep sequencing studies indicating that nearly 20% of human tumours harbour mutations in G-protein-coupled receptors (GPCRs) and the implications for GPCRs as therapeutic targets in oncology. Full Text The good, the bad and the ugly – TFH cells in human health and disease doi:10.1038/nri3447 An increasing number of studies have highlighted new aspects of the differentiation and function of T follicular helper (TFH) cells in disease, which might represent targets for novel therapeutics. Full Text Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling doi:10.1038/nature12205 Interfering with binding of PDEδ to KRAS with small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Full Text Drug Discovery JOBS of the week Senior Analyst (m / f) Global Governance in Drug Development and Medical, Strategy & Business Operations Merck Group Scientist / Sr Scientist � Oncology Drug Discovery H3 Biomedicine PhD Studentship on Noninvasive and Localised Control of Vascular Permeability for Ultrasound-Enhanced Drug Delivery Imperial College London Associate Director - Small Molecule Oncology Drug Discovery Johnson & Johnson Drug Discovery Opportunities at D. E. Shaw Research D. E. Shaw Research More Science jobs from Drug Discovery EVENT Comprehensive Overview of FDA Regulatory Compliance for Drug and Biotech Products 19.-20.09.13 Berlin, Germany More science events from Careers Top Career snapshots archive Career snapshots feature people associated with drug discovery and drug development, with the aim of providing expert insights and advice on a wide range of positions and career paths in this field. 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