Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases.

By T. Ishizaki, M. Uehata, I. Tamechika, Jeongsin Keel, Kimiko Nonomura, M. Maekawa, S. Narumiya. Molecular Pharmacology, 2000

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Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide++ + dihydrochloride] is widely used as a specific inhibitor of the Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases. This study examined the inhibition mechanism and profile of actions of Y-27632 and a related compound, Y-30141 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(1H-pyrrolo[2, 3-b]pyridin-4-yl)cyclohexan-ecarboxamide dihydrochloride]. Y-27632 and Y-30141 inhibited the kinase activity of both ROCK-I and ROCK-II in vitro, and this inhibition was reversed by ATP in a competitive manner. This suggests that these compounds inhibit the kinases by binding to the catalytic site. Their affinities for ROCK kinases as determined by K(i) values were at least 20 to 30 times higher than those for two other Rho effector kinases, citron kinase and protein kinase PKN. [(3)H]Y-30141 was taken up by cells in a temperature- and time-dependent and saturable manner, and this uptake was competed with unlabeled Y-27632. No concentrated accumulation was found, suggesting that the uptake is a carrier-mediated facilitated diffusion. Y-27632 abolished stress fibers in Swiss 3T3 cells at 10 microM, but the G(1)-S phase transition of the cell cycle and cytokinesis were little affected at this concentration. Y-30141 was 10 times more potent than Y-27632 in inhibiting the kinase activity and stress fiber formation, and it caused significant delay in the G(1)-S transition and inhibition of cytokinesis at 10 microM.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4bcb616b3aa023944bc36a46d7fa2565c521195f

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Citations in the corpus

Rho Kinase Inhibition Enhances Axonal Regeneration in the Injured CNS (2003, background): “The activity of ROCK-I and ROCK-II can be inhibited with the pyridine derivative Y-27632 (Uehata et al., 1997; Ishizaki et al., 2000).”
A Computational Tool for Quantitative Analysis of Vascular Networks (2011, methodology): “Y27632-treated explants contained areas with characteristically enlarged vessels, often juxtaposed to very fine vessels; the extent of these features was variable between individual Y27632-treated explants.”
Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. (2000, background): “For example, disrupting the actin cytoskeleton using cytochalasins and simply inhibiting cytoskeletal tension generation without altering cell shape using pharmacological modulators of actomyosin-based contractility both produce a block in G1 progression similar to that induced by cell rounding [26,”