Kinases

A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors. Aronov, A. M. & Bemis, G. W. Proteins 57, 36–50 (2004)

Fragment-based approaches to lead discovery, in which low-affinity, low-molecular-mass chemical 'fragments' are combined to give high-affinity leads, are becoming increasingly popular. Aronov and Bemis present a novel fragment-based approach to the discovery of kinase inhibitors, which utilizes an analysis of the structures of ∼40,000 known kinase inhibitors that indicates that their structures can be largely described by a small number of rings and linkers.

Biotechnology

Antidote-mediated control of an anticoagulant aptamer in vivo. Rusconi, C. P. et al. Nature Biotechnol. 17 Oct 2004 (doi:10.1038/nbt1023)

Current agents used to inhibit pathological blood clotting have to be carefully monitored to reduce the risk of serious bleeding. However, with the exception of heparin, no anticoagulants have a rapidly acting 'antidote' that can neutralize such side effects if they occur. Rusconi and colleagues describe an aptamer targeted at coagulation factor IXa, which has anticoagulant effects in animals that can be rapidly reversed using a rationally designed oligonucleotide antidote.

Lung diseases

Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis. Daniels, C. E. et al. J. Clin. Invest. 114, 1308–1316 (2004)

Profibrotic cytokines, such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), are thought to be important in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive and fatal fibrotic disease of the lungs. Daniels et al. provide data that indicate that fibroblasts respond to TGF-β by stimulating c-ABL kinase activity. Furthermore, imatinib (Gleevec; Novartis), which inhibits ABL family kinases and the PDGF receptor tyrosine kinase, was shown to obviate fibrotic changes in a mouse model of pulmonary fibrosis, and so could be a potential therapy for IPF.

Antithrombotic drugs

Disruption of protein–membrane binding and identification of small-molecule inhibitors of coagulation factor VIII. Spiegel, C. P. et al. Chem. Biol. 11, 1413–1422 (2004)

Highly specific interactions between proteins and lipid membranes are essential in many biological pathways and processes; for example, the interaction between factor VIII and the membranes of platelets has a key role in blood coagulation. Spiegel and colleagues have developed an enzyme-linked-immunosorbent-assay (ELISA)-based high-throughput screen, which they used to identify small molecules that inhibit the binding of factor VIII to lipid membranes. These compounds could be leads for the development of novel antithrombotic drugs.