Reviews & Analysis

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.

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.

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.

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.

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to the co-development of targeted cancer therapies and companion diagnostics that were not covered in depth in the draft guidance released by the US Food and Drug Administration in 2011.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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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'.