Anticancer drugs

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. Hurwitz, H. et al. N. Engl. J. Med. 350, 2335–2342 (2004)

Bevacizumab is an antibody against vascular endothelial growth factor, a key regulator of normal and abnormal blood-vessel growth, which, in February this year, became the first agent designed to inhibit tumour angiogenesis to be approved by the FDA. This paper reports the results of a key Phase III trial that formed part of the basis for the approval of bevacizumab, which showed that adding bevaciuzmab to chemotherapy significantly improves survival among patients with previously untreated metastatic colorectal cancer.

Lead identification

Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein–protein interactions. Raimundo, B. C. et al. J. Med. Chem. 47, 3111–3130 (2004)

Identification of a small molecule that inhibits herpes simplex virus DNA polymerase subunit interactions and viral replication. Pilger, B. D., Cui, C. & Coen, D. M. Chem. Biol. 11, 647–654 (2004)

Identifying inhibitors of protein-protein interactions has long been viewed as highly challenging, but significant progress has been made in this endeavour recently. In the first of these two papers, Raimundo and colleagues report a fragment-based approach to the discovery of a 60-nM inhibitor of the interaction of interleukin-2 (IL-2) and the IL-2 receptor, which is a therapeutic target for immune disorders. And in the second paper, Pilger et al. describe the development of a fluorescence-based high-throughput screen for inhibitors of an interaction between subunits of the herpes simplex virus DNA polymerase, and the identification of a small-molecule inhibitor that could provide a starting point for a new class of antiviral drugs.

Imaging

Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Smith-Jones, P. S. et al. Nature Biotechnol. 22, 701–706 (2004)

Many inhibitors of key signalling pathways involved in cancer are now in clinical trials, and a few have shown considerable success. However, in general, the clinical development of such agents has been hampered by the difficulty of assessing the effect of an agent on its target in patients. The authors of this paper describe a method for non-invasively imaging the pharmacodynamics of 17-allylaminogeldanamycin (17-AAG) — an Hsp90 inhibitor that is in Phase I trials as an anticancer agent — in mice, which could in principle be easily adapted for human use.