GSK269962A

Orally available, potent and selective ROCK1/2 inhibitor that impacting vasodilation and AML cell viability; selective probe for Rho-kinase signaling pathways.
GSK269962A (GSK269962) is a potent (ROCK1 IC50 1.6 nM; ROCK2 IC50 4-6 nM), selective, orally bioavailable inhibitor of ROCK kinases. Offering greater selectivity than Y-27632 and Fasudil, it weakly inhibits MSK1 (IC50 49 nM) and RSK1 (IC50 132 nM). As an ATP-competitive inhibitor, it blocks ROCK-mediated phosphorylation of downstream targets (e.g., MLC, MYPT1), causing significant functional outcomes including smooth muscle relaxation (vasorelaxation IC50 35 nM), actin stress fiber disruption, G2 cell cycle arrest, and apoptosis, notably in AML models (proliferation IC50 0.61-1337 nM). In vitro, it inhibits AngII-induced stress fibers and inflammatory cytokine production. With demonstrated in vivo efficacy lowering blood pressure in hypertensive rats and reducing leukemia burden in AML xenografts, GSK269962A serves as a valuable tool for studying ROCK signaling in cytoskeleton regulation, smooth muscle contraction, cell migration, proliferation, and survival.