University of Houston Molecular Medicine & Experimental Therapeutics: Craft Subgroup
::ROCK and Rho
Heart failure is the leading cause of combined morbidity and mortality in the United States. It remains an incurable disease process with an estimated two-year mortality of 30-50% for the patients with advanced disease. Although advances in the treatment for failing heart have been made, our understanding of the molecular mechanism leading to heart failure is still limited. The Schwartz lab showed that proliferative fibroblasts derived from monocytic, blood-borne precursor cells play a critical role in fibrosis in a murine ischaemic/reperfusion cardiomyopathy (I/RC) model of heart disease. Schwartz and collaborators have shown that down regulation of Rho Associated Kinase-1 (ROCK1) blocked the movement of monocytes from the coronary blood vessels into the heart to form myofibroblasts reducing fibrosis. ROCK1 null mice did not develop cardiac fibrosis and dysfunction, identifying a powerful rationale to develop ROCK1 inhibitors for the treatment of disease. We discovered an inhibitory compound which blocked ROCK1 activity in the presence of 1mM ATP. This compound's binding epitope on ROCK1 was mapped using chemical cross-linking to the Activation Loop, a novel locus to direct a new class of inhibitory drugs. We further are evaluating the compound in an aortic ring contractility assay. These results indicate that our lead compounds or derivatives are candidates in therapies directed against a number of important diseases such as heart disease, pulmonary hypertension, arterial hypertension, gluacoma management, insulin resistance, kidney disease, hemolytic anemia, stroke, ischemia reperfusion injury, or acute mycloid leukemia.
Figure 1: We are developing lead compound that bind to the activation loop rather then the active site like other inhibitors such as Y27632.
