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

0507922 - ÚEB 2020 RIV US eng J - Journal Article
Voller, Jiří - Zahajská, Lenka - Plíhalová, Lucie - Jeřábková, Jana - Burget, David - Pataki, A.C. - Kryštof, Vladimír - Zatloukal, M. - Brábek, J. - Rösel, D. - Mik, V. - Tkáč, Martin - Pospíšil, T. - Gucký, T. - Doležal, Karel - Strnad, Miroslav
6-Substituted purines as ROCK inhibitors with anti-metastatic activity.
Bioorganic Chemistry. Roč. 90, SI (2019), č. článku 103005. ISSN 0045-2068. E-ISSN 1090-2120
R&D Projects: GA MŠMT(CZ) LO1204; GA MŠMT(CZ) LO1304; GA MŠMT(CZ) LQ1604; GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR GA17-14007S
Institutional support: RVO:61389030
Keywords : Anti-metastatic activity * Melanoma * Protein kinase inhibitor * rock
OECD category: Oncology
Impact factor: 4.831, year: 2019
Method of publishing: Open access
http://dx.doi.org/10.1016/j.bioorg.2019.103005

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.
Permanent Link: http://hdl.handle.net/11104/0298915