Volume 5 Issue 9, September 2006

In June 2006, the tyrosine kinase inhibitor dasatinib (Sprycel; Bristol-Myers Squibb) was approved by the US FDA for the treatment of adults with chronic myeloid leukaemia and Philadelphia-chromosome-positive acute lymphoblastic leukaemia with resistance or intolerance to previous therapy, including the kinase inhibitor imatinib (Gleevec; Novartis).

The open-source software movement has successfully pioneered several strategies that might also be applicable in drug discovery and development. Munos considers the challenges involved, and proposes a model to harness the potential of open-source drug R&D.

Pharmacological activity depends on the binding of drugs to their targets. Copelandet al. provide a perspective on the importance of residence time for lead optimization and describe the potential advantages of drugs with a long residence time, in terms of duration of pharmacological effects and selectivity.

The poor predictive ability of traditional xenograft mouse models is thought to be a key factor underlying failures of novel cancer drugs in clinical trials. Sharpless and DePinho describe the opportunities and challenges in the application of novel genetically engineered mouse models that more faithfully mimic human cancers, and their potential to improve the success of cancer drug development.

Evgenovet al. review the discovery, biochemistry and pharmacology of nitric oxide-independent stimulators and activators of soluble guanylate cyclase, a key signal-transduction enzyme, and discuss their potential for treating arterial and pulmonary hypertension, heart failure, atherosclerosis, thrombosis, erectile dysfunction, renal fibrosis and failure, and liver cirrhosis.

Johnstone and colleagues discuss the molecular events that underlie the anticancer effects of histone deacetylase inhibitors, and consider how the clinical development and application of these agents may be optimized, either as monotherapies or in combination with other anticancer drugs.

Far from being simple degradative enzymes, proteases are now seen as key signalling molecules and desirable drug targets in several diseases. Turk discusses our success so far at targeting proteases and how these enzymes might be exploited therapeutically in the future.