ONCOLOGY

Cancer is the second most common cause of death in the United States, with more than 1,350,000 new cases diagnosed every year. Kinases are attractive anticancer targets: three inhibitors of signaling kinases (Iressa®, Gleevec® and Tarceva™) were recently approved for clinical use. Numerous downstream kinases (AKT, FAK, mTOR, ROCK and others) are targeted by various pharmaceutical companies for their potential role in tumor growth and drug resistance.

The Rho-ROCK signaling pathway is a particularly good target for the development of new, first-in-class oncology drugs: the pathway is activated in many tumors and this activation correlates with disease progression. ROCK (Rho-Associated Kinase) regulates actin cytoskeleton, cell shape, adhesion, and motility, both directly and through regulation of other kinases (FAK, LIMK, etc.). ROCK activity is essential for both tumor metastasis (via its role in invasion and motility of tumor cells) and growth (via its potential role in the angiogenesis).

Currently, there are no anti-cancer drugs on the market that work through inhibition of ROCK.

SLx-2119 is a potent, selective ROCK2 inhibitor that is being developed for oncology. The selectivity for ROCK2 means that the acute hemodynamic effects associated with mixed ROCK1/ROCK2 inhibitors are avoided. SLx-2119 inhibits stress fiber formation, cellular migration, and endothelial cell tube formation in vitro, and inhibits angiogenesis in Matrigel® plug assays in vivo, establishing its activity as a ROCK2 inhibitor in cells and in vivo. The compound is orally available and has demonstrated excellent preclinical activity in several mouse xenograft models (HT-1080, Panc-1, MDA-MB-231 cancer cell lines) and in a primary human tumor explant xenograft (mesenchymal chondrosarcoma). SLx-2119 will enter clinical development in the second quarter of 2007.