Reviews & Analysis

Hypertrophy of heart cells stimulated by pathological stress from cardiovascular disease increases the risk of morbidity and mortality, and inhibition of such hypertrophy is attracting increasing attention as a therapeutic strategy. McKinsey and Kass provide a comprehensive summary of small-molecule inhibitors of cardiac hypertrophy and intracellular signalling pathways that offer further promising therapeutic targets.

Toxicity is a leading cause of attrition at all stages of the drug development process. In their Review, Kramer and colleagues discuss how the early application of preclinical safety assessment can aid the design of safer pharmaceutical lead candidates.

Peroxynitrite — the product of the reaction of nitric oxide with superoxide radical — is a potent inducer of cell death. Szabó and colleagues review the biochemistry and pathophysiology of peroxynitrite and discuss pharmacological strategies to attenuate its toxic effects, which have lead to potential drug development candidates for cardiovascular, inflammatory and neurodegenerative diseases.

Embryonic stem cells (ESCs) can be used as a source of cellular models for a wide range of adult differentiated cells, providing that reliable differentiation protocols are established. Here, Pouton and Haynes discuss challenges and opportunities regarding the use of ESC-derived models for drug discovery.

Protein-fragment complementation assays (PCAs) can be used to explore the dynamics of protein–protein interactions, and regulatory responses to intrinsic or extrinsic perturbations of biochemical pathways. Michnick and colleagues discuss the rationale behind the PCA design, and its manifold applications for drug discovery.

Members of the RAS superfamily of monomeric GTPases are promising anticancer targets, but previous attempts to therapeutically modulate their activity, which have focused on the development of farnesyltransferase inhibitors, have not proved as successful as hoped. The authors discuss novel approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.

With the development of genome-wide RNAi approaches, the cost and time involved in target identification, validation and other aspects of drug discovery could be significantly reduced. Ashworth and colleagues review technologies available for RNAi screens and discuss how cancer drug discovery can benefit from their application.

Few truly innovative drugs for central nervous system (CNS) disorders have been approved in recent years, suggesting that there is a need for strategies to improve the productivity of research and development in this field. The authors describe approaches that are being taken to discover CNS drugs, discuss their relative merits and consider how risk can be balanced and attrition reduced.

The scientific and regulatory issues associated with the possible introduction of 'follow-on' versions of protein drug products are currently attracting much attention. Past examples are discussed of the FDA's actions involving the evaluation of various types of follow-on and second-generation protein products and within-product manufacturing changes with a view to illustrating the FDA's scientific reasoning in this area.

The cellular microenvironment plays a critical role in cellular responses to therapy. A greater understanding of the extracellular matrix (ECM) and ECM–cell interactions could facilitate the design of novel drug delivery systems for biomacromolecular therapies, and interventions to manipulate the microenvironment may further improve the efficiency of such therapies.

Aggregation of hyperphosphorylated tau is involved in neurodegeneration in Alzheimer's disease and other disorders. The authors discuss the progress in the design of selective kinase inhibitors that suppress tau hyperphosphorylation as a therapeutic strategy for neurodegenerative tauopathies.

RNA interference (RNAi) has rapidly advanced since its initial discovery to form the basis of a new class of therapeutics. De Fougerolles and colleagues discuss the challenges in the development of RNAi-based therapeutics, focusing on lead identification/optimization and effective delivery, and review the latest clinical results.

Although clinical trials using matrix metalloproteinase inhibitors (MMPIs) for cancer therapy were disappointing, Opdenakker and colleagues discuss how the use of selective MMPIs might lead to new treatments for acute and chronic inflammatory and vascular diseases.

Dual-specificity phosphatases (DUSPs) are a subclass of protein tyrosine phosphatases (PTPs) that interact with and regulate mitogen-activated protein kinases (MAPKs). DUSPs can positively or negatively control immune responses in cancers, infectious diseases and inflammatory diseases, making them promising drug targets for immune-based disorders.

Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases, including cancer. Reichert and Valge-Archer overview trends in the development and regulatory approval of anticancer monoclonal antibodies since 1980, with the aim of informing future research and development for this class of therapeutics.

Ten years after the cloning of the capsaicin TRPV1 receptor, TRPV1 antagonists are currently in clinical trials for the treatment of pain. Szallasi and colleagues review the past decade of progress and discuss how TRPV1 antagonists could be beneficial in other disorders.

Endogenous polyamines are essential for cell growth and are known to be dysregulated in cancer and other diseases. Here the potential strategies for modulating polyamine metabolism and function are reviewed with a focus on the use of synthetic polyamine analogues.

Peptide epitopes represent the minimal immunogenic region of a protein antigen. In the light of new insights into the nature of immunogenic epitopes, and recent advances in peptide delivery, stability and design, Purcell and colleagues review developments in the field of peptide-based vaccines.

Pathological angiogenesis plays a role in a wide range of diseases. Folkman argues that viewing angiogenesis as an 'organizing principle' in biology can lead to novel insights into the molecular mechanisms of seemingly unrelated phenomena, and facilitate the development of new therapeutic approaches.

In this Review, Pettipher and colleagues discuss antagonism of DP₁ and CRTH2 prostaglandin D₂receptors as an approach to treat allergic diseases. They also review recent progress in the discovery and development of selective antagonists of these receptors.