Kinase inhibitors

Discovery of S -[5-amino-1-(4-fluorophenyl)-1 H -pyrazol-4-yl]-[3-(2,3-dihydropropoxy)phenyl]-methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase. Goldstein, D. M. et al. J. Med. Chem. 49, 1562–1575 (2006)

Goldstein et al. describe the optimization of a series of p38 inhibitors identified by high-throughput screening. X-ray crystal structures of the series bound to p38 revealed the presence of a hydrogen bond between the inhibitor and a threonine residue in the ATP-binding site of p38 that contributes to inhibitor selectivity. This information was used to guide lead optimization, which resulted in a highly selective and orally bioavailable p38 inhibitor with anti-inflammatory activity in cell-based assays.

Osteoporosis

Denosumab in postmenopausal women with low bone mineral density. McClung, M. R. et al. New Engl. J. Med. 354, 821–831 (2006)

Osteoclasts, cells that resorb bone, are regulated by receptor activator of nuclear factor-κB ligand (RANKL). This paper reports Phase II trial results in which denosumab, a human monoclonal antibody that targets RANKL and blocks its effects on osteoclasts, was found to increase bone density and decrease bone resorption in a dose-dependent manner.

Gene therapy

Effective gene therapy with nonintegrating lentiviral vectors. Yàñez-Muñoz, R. J. et al. Nature Med. 12, 348–353 (2006)

Gene therapy has been hindered in part by the risk that vector integration into host chromosomes might cause mutations that can lead to cancer and lymphoproliferative diseases. This paper now provides the first in vivo evidence of sustained stable transgene expression in rat ocular and brain tissues using an integration-deficient vector, and reports the use of this approach to halt the progression of ocular degeneration in rats.

Neurological disorders

Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Flavell, S. W. et al. Science 311, 1008–1012 (2006)

A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Shalizi, A. et al. Science 311, 1012–1017 (2006)

The transcription factor myocyte enhancer factor-2 (MEF2) has emerged as a possible new target for neurological diseases that involve changes in synaptic formation and plasticity, according to two recent reports. The first paper shows that when neuronal activity is increased, the resulting calcium influx into cells causes calcineurin to dephosphorylate and activate MEF2, subsequently upregulating a set of genes that restrict synapse formation. The second paper further dissects the mechanism by which calcineurin regulates MEF2, and implicates MEF2 signalling in the post-synaptic differentiation of dendrites, which is essential for synapse formation. Both papers identify MEF2 as a new transcription factor with possible therapeutic relevance for Alzheimer's disease and autism.