6-Substituted purines as ROCK inhibitors with anti-metastatic aktivity

Voller J., Zahajská L., Plíhalová L., Jeřábková J., Burget D., Pataki A.C., Kryštof V., Zatloukal M., Brábek J., Rösel D., Mik V., Tkáč M., Pospíšil T., Gucký T., Doležal K., Strnad M.

Keywords: Protein kinase inhibitor, ROCK, Anti-metastatic activity, Melanoma
Abstract: Rho-associated serine/threonine kinases (ROCKs) are principal regulators of the actin cytoskeleton that regulate the contractility, shape, motility, and invasion of cells. We explored the relationships between structure and anti-ROCK2 activity in a group of purine derivatives substituted at the C6 atom by piperidin-1-yl or azepan-1-yl groups. Structure-activity relationship (SAR) analyses suggested that anti-ROCK activity is retained, and may be further increased, by substitution of the parent compounds at the C2 atom or by expansion of the C6 side chain. These inhibitors of ROCK can reach effective concentrations within cells, as demonstrated by a decrease in phosphorylation of the ROCK target MLC, and by inhibition of the ROCK-dependent invasion of melanoma cells in the collagen matrix. Our study may be useful for further optimization of C6-substituted purine inhibitors of ROCKs and of other sensitive kinases identified by the screening of a broad panel of protein kinases.
IEB authors: Karel Doležal, Hana Jeřábková, Vladimír Kryštof, Lucie Plíhalová, Miroslav Strnad, Jiří Voller, Lenka Zahajská