• Opinion |

    Analysis of the role of synthetic organic chemistry in the identification of chemical starting points for drug discovery and subsequent optimization into candidate drugs indicates that a small number of reactions and commercially available building blocks dominate. This Perspective highlights opportunities for expanding the synthetic toolbox of medicinal chemists, potentially enabling the more effective exploration of therapeutically relevant chemical space.

    • Jonas Boström
    • , Dean G. Brown
    • , Robert J. Young
    •  & György M. Keserü
  • Opinion |

    Dysregulation of the endocannabinoid system has been implicated in numerous diseases, particularly pain, psychiatric and neurological disorders, but therapeutic intervention in this complex system has proved challenging. In this Perspective article, Di Marzo discusses the lessons learned from the development of drugs that alter endocannabinoid signalling and highlights novel opportunities for pharmacologically manipulating the endocannabinoid system, such as the use of multi-target drugs.

    • Vincenzo Di Marzo
  • Opinion |

    Recent studies have indicated the potential to develop small-molecule drugs that act on RNA targets, leading to burgeoning interest in the field. This article discusses general principles for discovering small-molecule drugs that target RNA and argues that the overarching challenge is to identify appropriate target structures in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets.

    • Katherine Deigan Warner
    • , Christine E. Hajdin
    •  & Kevin M. Weeks
  • Opinion |

    There has been a resurgence in interest in phenotypic drug discovery (PDD) approaches in recent years based on their potential to address the incompletely understood complexity of diseases and their promise of delivering first-in-class drugs. However, PDD approaches can also present considerable challenges, and this article focuses on the lessons learned by researchers engaged in PDD in the pharmaceutical industry, and discusses how PDD can best deliver value to drug discovery portfolios.

    • John G. Moffat
    • , Fabien Vincent
    • , Jonathan A. Lee
    • , Jörg Eder
    •  & Marco Prunotto
  • Opinion |

    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.

    • 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
  • Opinion |

    Non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, thereby representing potential drug targets. Here, Matsui and Corey assess the potential and challenges in therapeutically exploiting ncRNA species — including microRNA, intronic RNA, repetitive RNA and long ncRNA — highlighting key lessons learned during the development of technologies targeting mRNA.

    • Masayuki Matsui
    •  & David R. Corey
  • Opinion |

    This article discusses evolving preclinical strategies for detecting drug-induced cardiotoxicity using human ion-channel assays, human-basedin silicoreconstructions and human stem cell-derived cardiomyocytes. Such strategies have the potential to improve the early detection of genuine cardiotoxicity risks, reducing the likelihood of mistakenly discarding viable drug candidates and speeding worthy drugs into clinical trials.

    • Gary Gintant
    • , Philip T. Sager
    •  & Norman Stockbridge
  • Opinion |

    Members of the integrin family of receptors, which are involved in cell–cell adhesion, have been successfully targeted for cardiovascular disease, multiple sclerosis and inflammatory bowel disease. Ley and colleagues review the biological basis for the development of the next generation of integrin-targeted drugs, highlighting lessons learned from successes and failures.

    • Klaus Ley
    • , Jesus Rivera-Nieves
    • , William J. Sandborn
    •  & Sanford Shattil
  • Opinion |

    Modulators of glucagon-like peptide 1 (GLP1) and the resulting G protein-coupled receptor (GPCR) signalling have recently come to the fore of the treatment of type 2 diabetes. In this Opinion article, Oh and Olefsky discuss the potential for intervention with other GPCRs for the treatment of this disease, highlighting GPCR-mediated effects on insulin secretion, insulin sensitivity and inflammation.

    • Da Young Oh
    •  & Jerrold M. Olefsky
  • Opinion |

    The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype — epithelial–mesenchymal transition — has a key role in tumour progression and is therefore becoming a promising anticancer target. This article discusses the screening and classification of compounds that affect epithelial–mesenchymal transition, highlights some compounds of particular interest and discusses issues related to their clinical application.

    • Fabrizio Marcucci
    • , Giorgio Stassi
    •  & Ruggero De Maria
  • Opinion |

    Over the past decade, the drug–target residence time model has been broadly applied to drug discovery programmes across multiple therapeutic areas. To mark the 10 year anniversary of this model, Copeland discusses the benefits of assessing residence time, highlighting some of the advances in its theory and application.

    • Robert A. Copeland
  • Opinion |

    A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. This article discusses the progress with two pioneering initiatives — one involving the UK Medical Research Council and one involving the US National Center for Advancing Translational Sciences — and the unique requirements and challenges for this model.

    • Donald E. Frail
    • , Madeleine Brady
    • , K. Jane Escott
    • , Alison Holt
    • , Hitesh J. Sanganee
    • , Menelas N. Pangalos
    • , Chris Watkins
    •  & Craig D. Wegner
  • Opinion |

    Drug resistance is threatening to sideline the currently available antibiotics, and new antibiotics are unlikely to become available before the current arsenal becomes ineffective. Brown proposes the use of approved drugs or neutraceuticals as antibiotic resistance breakers — compounds that could be administered alongside current antibiotics to prolong their useful lifespan — to bridge the gap.

    • David Brown
  • Opinion |

    The quality of the chemical starting points for small-molecule drug discovery is a key factor in improving the likelihood of clinical success. In this article, experts from several organizations involved in drug discovery for malaria, tuberculosis and neglected tropical diseases present disease-specific criteria for hits and leads, and discuss the underlying rationale.

    • Kei Katsuno
    • , Jeremy N. Burrows
    • , Ken Duncan
    • , Rob Hooft van Huijsduijnen
    • , Takushi Kaneko
    • , Kiyoshi Kita
    • , Charles E. Mowbray
    • , Dennis Schmatz
    • , Peter Warner
    •  & B. T. Slingsby
  • Opinion |

    Incentives are increasingly available for the development of new drugs to tackle antibiotic resistance, but major scientific challenges remain, such as achieving penetration into bacteria. Tommasi and colleagues describe AstraZeneca's experiences in antibacterial drug discovery over the past decade using both target-based and phenotypic screening approaches, and discuss the reasons for failure as well as strategies to improve cytoplasmic penetration.

    • Ruben Tommasi
    • , Dean G. Brown
    • , Grant K. Walkup
    • , John I. Manchester
    •  & Alita A. Miller
  • Opinion |

    Epigenetic mechanisms of gene regulation have an important role in brain development, and evidence is accumulating that some neurological, psychiatric and behavioural disorders can be triggered or maintained by epigenetic means. In this Perspective article, Moshe Szyf explores the epigenetic basis of disorders of the central nervous system (CNS) and discusses strategies for the development of epigenetic-targeted drugs for CNS indications, as well as the particular challenges associated with this approach.

    • Moshe Szyf
  • Opinion |

    Efficient and reliable ways to predict drug metabolism early in the drug discovery process are important in reducing the risk of costly later-stage attrition. Schneider and colleagues summarize the state of the art in experimental and computational approaches for investigating drug metabolism, and discuss strategies to harness the potential synergies between them.

    • Johannes Kirchmair
    • , Andreas H. Göller
    • , Dieter Lang
    • , Jens Kunze
    • , Bernard Testa
    • , Ian D. Wilson
    • , Robert C. Glen
    •  & Gisbert Schneider
  • Opinion |

    Thermodynamic profiling of protein–ligand binding is increasingly used during lead optimization to find ligands that bind with high affinity. In this Perspective, Gerhard Klebe discusses the importance of water, hydrogen bonds, lipophilic contacts and residual mobility in protein–ligand binding, and considers how knowledge of the influence of these factors on the enthalpic and entropic components of the resulting thermodynamic signature can be used in drug design.

    • Gerhard Klebe
  • Opinion |

    Drug delivery methods that use targeted polymeric nanoparticles have the potential to increase local concentrations of a drug while reducing off-target accumulation. To best achieve this goal, Saltzman and colleagues argue that a holistic approach should be taken, in which anatomical, molecular and temporal aspects of the nanoparticle, drug and disease are taken into consideration.

    • Christopher J. Cheng
    • , Gregory T. Tietjen
    • , Jennifer K. Saucier-Sawyer
    •  & W. Mark Saltzman
  • Opinion |

    Potential drug–drug interactions mediated by ATP-binding cassette (ABC) and solute carrier (SLC) transporters are of clinical and regulatory concern, but the endogenous function of these drug transporters is unclear. Nigam describes the evidence that these transporters transport diverse endogenous substrates and could potentially be important in remote communication. Understanding such functions could clarify the roles of these transporters in disease and in drug–metabolite interactions.

    • Sanjay K. Nigam
  • Opinion |

    Caloric restriction can promote health and extend the lifespan of model organisms, and diverse classes of compounds that mimic the biochemical and functional effects of caloric restriction have attracted considerable interest as potential pharmacotherapies for diseases such as diabetes and obesity. Kroemer, Madeo and colleagues propose a unifying definition of caloric restriction mimetics as agents that induce autophagy by promoting protein deacetylation, which could have implications for their development as drugs.

    • Frank Madeo
    • , Federico Pietrocola
    • , Tobias Eisenberg
    •  & Guido Kroemer
  • Opinion |

    Over the past decade, cancer stem cells have emerged as the centerpiece of cancer research, having a major role in resistance to conventional therapy and in the metastatic spread of tumours. The authors discuss the biological complexity of this subpopulation of cells within tumours and explore novel means to tackle them therapeutically based on our current understanding.

    • Diwakar R. Pattabiraman
    •  & Robert A. Weinberg
  • Opinion |

    Agents that target tumour-supportive cellular machineries, such as the proteasome, heat shock protein complexes and proteins involved in chromatin modifications, are emerging as a new wave of anticancer drugs. Here, Dobbelstein and Moll provide their perspective on the advantages and limitations of these agents compared with established drugs that target DNA replication or signalling proteins such as kinases.

    • Matthias Dobbelstein
    •  & Ute Moll
  • Opinion |

    Regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, Eichler and colleagues discuss the consequences of regulatory risk-aversion and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

    • Hans-Georg Eichler
    • , Brigitte Bloechl-Daum
    • , Daniel Brasseur
    • , Alasdair Breckenridge
    • , Hubert Leufkens
    • , June Raine
    • , Tomas Salmonson
    • , Christian K. Schneider
    •  & Guido Rasi
  • Opinion |

    Here, the authors discuss issues relating to the co-development of targeted cancer therapies and companion diagnostics that were not covered in depth in the draft guidance released by the US Food and Drug Administration in 2011. They propose potential strategies that will be useful to mitigate challenges and to help guide the future co-development of drugs and diagnostics.

    • Jane Fridlyand
    • , Richard M. Simon
    • , Jessica C. Walrath
    • , Nancy Roach
    • , Richard Buller
    • , David P. Schenkein
    • , Keith T. Flaherty
    • , Jeff D. Allen
    • , Ellen V. Sigal
    •  & Howard I. Scher
  • Opinion |

    There is substantial debate over the best approach for developing transformative drugs and how this might be supported. To help inform this debate by improving the understanding of the characteristics of transformative drug innovation, the authors surveyed a US-based group of 180 expert physicians in 15 medical specialities, who identified the drugs that they considered to be the most transformative in their fields over the past 25 years, as well as key factors affecting their opinions.

    • Aaron S. Kesselheim
    •  & Jerry Avorn
  • Opinion |

    The therapeutic outcome of a drug or procedure is influenced by the placebo response in both drug development and clinical practice. Enck and colleagues examine how the placebo response can be utilized in these settings to ensure that the most desirable outcome is attained.

    • Paul Enck
    • , Ulrike Bingel
    • , Manfred Schedlowski
    •  & Winfried Rief
  • Opinion |

    Pharmacogenetics is an increasingly important tool for drug development, which has been reflected in recent guidelines from regulatory agencies on the application of pharmacogenetics in studies of investigational drugs. In this article, authors from Europe, the United States and Japan overview the guidelines from the regulatory agencies in each region and discuss the common themes and differences.

    • Marc Maliepaard
    • , Charity Nofziger
    • , Marisa Papaluca
    • , Issam Zineh
    • , Yoshiaki Uyama
    • , Krishna Prasad
    • , Christian Grimstein
    • , Michael Pacanowski
    • , Falk Ehmann
    • , Silvia Dossena
    •  & Markus Paulmichl
  • Opinion |

    The GPCR Network was established in 2010 with the aim of structurally characterizing 15–25 representative human G protein-coupled receptors (GPCRs) within 5 years; so far, more than eight have been determined. Here, Stevens and colleagues provide an overview of this collaborative effort and the challenges remaining in gaining detailed insights into the structure–function relationships of this receptor superfamily.

    • Raymond C. Stevens
    • , Vadim Cherezov
    • , Vsevolod Katritch
    • , Ruben Abagyan
    • , Peter Kuhn
    • , Hugh Rosen
    •  & Kurt Wüthrich
  • Opinion |

    In vitropharmacological profiling is playing an increasing part in identifying undesirable off-target effects of candidate drugs earlier in the drug discovery process. In this article, authors from four large pharmaceutical companies share their views on the rationale, strategies and methodologies forin vitropharmacological profiling, and recommend a minimal panel of targets for screening.

    • Joanne Bowes
    • , Andrew J. Brown
    • , Jacques Hamon
    • , Wolfgang Jarolimek
    • , Arun Sridhar
    • , Gareth Waldron
    •  & Steven Whitebread
  • Opinion |

    Preclinical research indicates that various drugs approved for indications such as hypertension and diabetes could also have potentially beneficial effects in Alzheimer's disease, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. This article presents a formal consensus evaluation of these drug repositioning opportunities, and highlights several compounds for which sufficient evidence is available to encourage further investigation and potential progression to clinical trials in Alzheimer's disease.

    • Anne Corbett
    • , James Pickett
    • , Alistair Burns
    • , Jonathan Corcoran
    • , Stephen B. Dunnett
    • , Paul Edison
    • , Jim J. Hagan
    • , Clive Holmes
    • , Emma Jones
    • , Cornelius Katona
    • , Ian Kearns
    • , Patrick Kehoe
    • , Amrit Mudher
    • , Anthony Passmore
    • , Nicola Shepherd
    • , Frank Walsh
    •  & Clive Ballard
  • Opinion |

    The therapeutic index of drug candidates — a quantitative relationship between their safety and efficacy, such as the ratio of the highest exposure to a drug that does not cause toxicity to the exposure that has the desired pharmacological effects — is widely used to aid decision-making in drug discovery and development. Muller and Milton discuss key issues in the calculation and interpretation of therapeutic indices at different stages of the process.

    • Patrick Y. Muller
    •  & Mark N. Milton
  • Opinion |

    Here, Lawson proposes that the use of antibodies as tools in small-molecule drug discovery — for example, to validate targets, enable crystallography and to constrain proteins for screening — could reduce risks and facilitate the modulation of traditionally intractable targets, such as protein–protein interactions.

    • Alastair D. G. Lawson
  • Opinion |

    Extensive analyses of successful and failed compounds in drug discovery and development have improved our understanding of the role of physicochemical properties in attrition. They have also clarified the difficulties in finding the 'sweet spot' in medicinal chemistry programmes. Hann and Keserü discuss scientific, strategic and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, and a wider appreciation of the risks of pursuing suboptimal compounds.

    • Michael M. Hann
    •  & György M. Keserü
  • Opinion |

    The number of new drugs approved per billion US dollars spent on research and development (R&D) has fallen around 80-fold in inflation-adjusted terms since 1950, despite advances in many of the scientific and technological inputs into the R&D process. Given the apparent lack of impact of proposed solutions to declining R&D efficiency so far, Scannell and colleagues ask whether the underlying problems have been correctly diagnosed and discuss factors that they consider to be the primary causes.

    • Jack W. Scannell
    • , Alex Blanckley
    • , Helen Boldon
    •  & Brian Warrington
  • Opinion |

    Biased ligands of seven-transmembrane receptors (also known as GPCRs), which preferentially activate specific signalling pathways associated with a given seven-transmembrane receptor (GPCR), could have novel therapeutic profiles. Here, the authors discuss which methods may be most appropriate to quantify bias in a drug discovery setting.

    • Terry Kenakin
    •  & Arthur Christopoulos
  • Opinion |

    This Perspective highlights the sources and functions as well as the evaluation of biomarkers that are useful in cancer, with a focus on those biomarkers that are most relevant for identifying patients who are likely to respond to a given therapy, and those biomarkers that are most effective for measuring patient response to therapy.

    • Gary J. Kelloff
    •  & Caroline C. Sigman
  • Opinion |

    Predictive biomarkers allow the identification of the subsets of patients who will benefit from a particular drug. However, the development of biomarker–drug combinations requires novel clinical trial designs. In their Perspective, Beckman and colleagues formulate guidelines for the adaptive integration of predictive biomarkers into Phase II/Phase III clinical trials and present strategies to achieve optimal efficiency of such trials.

    • Robert A. Beckman
    • , Jason Clark
    •  & Cong Chen
  • Opinion |

    Analysing data on bioactive compounds can provide insight for developing improved molecules, although much of this data currently resides in proprietary databases. However, even when such data is made available in research articles or public databases, key information is often missing, or the data is not in a format suited to data-mining. With the aim of addressing these issues, this article proposes reporting guidelines for bioactive entities, which have been developed by representatives from industry, academia and data resource providers.

    • Sandra Orchard
    • , Bissan Al-Lazikani
    • , Steve Bryant
    • , Dominic Clark
    • , Elizabeth Calder
    • , Ian Dix
    • , Ola Engkvist
    • , Mark Forster
    • , Anna Gaulton
    • , Michael Gilson
    • , Robert Glen
    • , Martin Grigorov
    • , Kim Hammond-Kosack
    • , Lee Harland
    • , Andrew Hopkins
    • , Christopher Larminie
    • , Nick Lynch
    • , Romeena K. Mann
    • , Peter Murray-Rust
    • , Elena Lo Piparo
    • , Christopher Southan
    • , Christoph Steinbeck
    • , David Wishart
    • , Henning Hermjakob
    • , John Overington
    •  & Janet Thornton
  • Opinion |

    The efficacy–effectiveness gap describes the difference in drug performance under clinical trial conditions versus real-life conditions. Here, the authors argue that this phenomenon is due to variability in drug responses. They discuss the underlying biological and behavioural reasons for this phenomenon and propose strategies to 'bridge the gap'.

    • Hans-Georg Eichler
    • , Eric Abadie
    • , Alasdair Breckenridge
    • , Bruno Flamion
    • , Lars L. Gustafsson
    • , Hubert Leufkens
    • , Malcolm Rowland
    • , Christian K. Schneider
    •  & Brigitte Bloechl-Daum
  • Opinion |

    Vessel normalization strategies aim to increase tumour perfusion and oxygenation, and have the potential to reduce metastasis and improve responses to conventional anticancer therapies. Here, Carmeliet and Jain discuss the benefits and limitations of this emerging new treatment paradigm for cancer and other angiogenic disorders.

    • Peter Carmeliet
    •  & Rakesh K. Jain
  • Opinion |

    G-quadruplexes are four-stranded DNA structures that appear to be over-represented in the promoter region of various genes, including oncogenes such asMYC and KRAS. This article discusses evidence indicating the possibility of therapeutically modulating the transcription of such genes through the targeting of G-quadruplexes with small molecules, and considers challenges and opportunities for the development of such molecules as anticancer drugs.

    • Shankar Balasubramanian
    • , Laurence H. Hurley
    •  & Stephen Neidle
  • Opinion |

    The reduction in attrition rates of cancer therapeutics in the clinic requires robust translational strategies. In their Perspective, Caponigro and Sellers review historical and current uses of preclinical model systems, and discuss how these systems can be optimized for rationally predicting the therapeutic benefit of drug candidates.

    • Giordano Caponigro
    •  & William R. Sellers
  • Opinion |

    Has high-throughput screening (HTS) been unfairly blamed one factor responsible for the decline in productivity in the pharmaceutical industry? This article discusses some common misconceptions about the nature and value of HTS, and argues in support of its importance as a key tool in the discovery of novel chemotypes in drug discovery and chemical biology.

    • Ricardo Macarron
    • , Martyn N. Banks
    • , Dejan Bojanic
    • , David J. Burns
    • , Dragan A. Cirovic
    • , Tina Garyantes
    • , Darren V. S. Green
    • , Robert P. Hertzberg
    • , William P. Janzen
    • , Jeff W. Paslay
    • , Ulrich Schopfer
    •  & G. Sitta Sittampalam
  • Opinion |

    The Fc (crystallizable fragment) region of therapeutic antibodies can have an important role in their safety and efficacy. This article summarizes the current knowledge of antibody Fc functionality, provides a strategy for assessing the effector functions of different classes of therapeutic antibodies and proposes a path for routine testing and controls for manufacturers of antibody products.

    • Xu-Rong Jiang
    • , An Song
    • , Svetlana Bergelson
    • , Thomas Arroll
    • , Bhavin Parekh
    • , Kimberly May
    • , Shan Chung
    • , Robert Strouse
    • , Anthony Mire-Sluis
    •  & Mark Schenerman
  • Opinion |

    Data on the fraction of protein-bound drug are frequently used to guide chemical structure design and to prioritize compounds forin vivostudies. Here, the authors highlight how these practices are misleading and could result in the wrong compounds being progressed through discovery programmes.

    • Dennis A. Smith
    • , Li Di
    •  & Edward H. Kerns
  • Opinion |

    Regulatory and economic incentives to develop drugs for rare diseases, known as orphan drugs, have resulted in substantial improvements in the treatment for patients with some such diseases. However, the advent of orphan drug development has also raised several questions, from the definition of rarity, to the pricing of orphan drugs and their impact on health-care systems. Tambuyzer considers such questions and related misconceptions with the aim of aiding future progress in the field.

    • Erik Tambuyzer
  • Opinion |

    Developing optimal combination strategies for molecularly targeted anticancer drugs is substantially more complex than for traditional chemotherapies. Here, Doroshow and colleagues discuss the lessons learned from the evaluation of combinations of molecularly targeted anticancer agents by the US National Cancer Institute (NCI), and highlight several new approaches that the NCI has initiated to improve the effectiveness of such combinations.

    • Shivanni Kummar
    • , Helen X. Chen
    • , John Wright
    • , Susan Holbeck
    • , Myrtle Davis Millin
    • , Joseph Tomaszewski
    • , James Zweibel
    • , Jerry Collins
    •  & James H. Doroshow
  • Opinion |

    Currently, drug development is based on a consecutive phase model and Phase I clinical trials often have tolerability as their primary objective. Here, Cohen advocates new concepts for drug development that are based on pharmacological knowledge about the effects of the drug and an adaptive, cyclical development process.

    • Adam F. Cohen
  • Opinion |

    The development of new protease inhibitors has proved challenging in recent years. In their Perspective, Drag and Salvesen discuss the underlying reasons for this, and how lessons learned from failures can inform future research directions in the field.

    • Marcin Drag
    •  & Guy S. Salvesen