ROCK2 Selectivity
The ROCKs impact cytoskeletal function through their ability to phosphorylate a range of proteins that directly regulate cytoskeletal proteins, including myosin light chain kinase, myosin light chain phosphatase, beta-catenin, cofilin, FAK and LIMK, and thus the ROCKs are positioned to play essential roles in the physiological and pathophysiological processes of various cell types. The ROCK enzymes exist as two isoforms, ROCK1 and ROCK2, which share 65% overall homology. Gene knockout and siRNA studies suggest that each isoform plays distinct roles in mammalian biology.

Non-selective inhibitors of ROCK (such as Y-27632 and fasudil) cause acute hypotension by relaxing vascular smooth muscle, which is associated with ROCK1/2 inhibition. In addition, ROCK1 knockout experiments suggest that inhibiting ROCK1 may also carry the risk of kidney toxicity. In contrast to non-selective inhibitors, Surface Logix’s proprietary ROCK2 inhibitors do not affect vascular tone or hemodynamic function. While some researchers are pursuing non-selective ROCK inhibition in hypertension and other cardiovascular indications (fasudil is marketed in Japan for acute treatment of cerebral vasospasm), Surface Logix believes the greater promise of ROCK inhibition lies in selectively interfering with ROCK2 activity.

Surface Logix’s ROCK program has succeeded in producing the only known inhibitors selective for ROCK2, which enables the company to pursue a range of promising indications without the potential for cardiovascular side effects associated with non-selective ROCK inhibitors.

Metabolic Disease / Obesity
SLx has demonstrated significant, non-CNS mediated weight loss with improved lipid and glucose metabolic profiles through the selective inhibition of ROCK2. Long term studies in rodents demonstrate both long term weight loss and safety of selective ROCK2 inhibition. Surface Logix’s most advanced ROCK2 inhibitor, SLx-2119, has recently been approved to begin first in man studies in metabolic disease.

Fibrosis
The ROCK signaling pathways are 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[3]. Inhibiting ROCK2 therefore represents a very attractive approach to interfering with the mechanisms underlying hepatic steatosis and fibrosis.

Glaucoma
The Rho-ROCK signal transduction pathway is involved in the regulation of aqueous humor outflow through the trabecular meshwork of the eye. Non-selective ROCK inhibitors have been shown to lower intraocular pressure as well as enhance retinal ganglion cell survival and axon regeneration[4]. Non-selective ROCK inhibitors applied to the eye have also been shown to cause hyperemia, a side effect that could be eliminated with a ROCK2-selective compound such as SLx-2119.

Preclinical Development
SLx-2119 has been evaluated in short and long term preclinical pharmacology studies, as well as in standard GLP pre-clinical tox and safety studies. An IND was filed in August, 2009 and first in human studies in metabolic disease will begin in October, 2009.