ONCOLOGY

Cancer is the second most common cause of death in the United States, with more than 1,350,000 new cases d iagnosed 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.

LIVER STEATOSIS/FIBROSIS

Non-alcoholic fatty liver disease (NAFLD), which is the most common disease of the liver, is fatty inflammation of the liver in the absence of excessive alcohol use. NAFLD covers a spectrum of disease states, from hepatic steatosis (fat accumulation in the liver) to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis of the liver (cirrhosis). The overall prevalence of NAFLD is estimated to be 20%, and the overall prevalence of NASH is estimated to be 3%. There is a strong association of both states with obesity and with type 2 diabetes. For example, 95% of patients with NASH are obese, and 55% of patients with NASH have type 2 diabetes.

The Rho-ROCK2 signaling pathway is a key enzyme system involved in liver steatosis and fibrosis. ROCK2 plays an important role in intracellular signaling pathways that lead to pro-inflammatory cytokine/chemokine production by macrophages, the activation of hepatic stellate cells (HSCs) and their differentiation into myofibroblasts, as well as the proliferation of the myofibroblasts themselves, which are the cell type ultimately responsible for fibrosis. Inhibiting ROCK2 therefore represents a very attractive approach to interfering with the mechanisms underlying hepatic steatosis and fibrosis.

SLx-2119 is a potent, selective ROCK2 inhibitor that is being developed for oncology and liver steatosis. 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) and in a murine liver steatosis model. SLx-2119 is currently in the IND preparation stage.