6-Substituted purines as ROCK inhibitors with anti-metastatic activity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31271944
DOI
10.1016/j.bioorg.2019.103005
PII: S0045-2068(18)31575-X
Knihovny.cz E-resources
- Keywords
- Anti-metastatic activity, Melanoma, Protein kinase inhibitor, ROCK,
- MeSH
- Protein Kinase Inhibitors chemical synthesis pharmacology MeSH
- rho-Associated Kinases antagonists & inhibitors MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Movement drug effects MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Purines chemical synthesis pharmacology MeSH
- Signal Transduction drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Protein Kinase Inhibitors MeSH
- rho-Associated Kinases MeSH
- Antineoplastic Agents MeSH
- Purines MeSH
- ROCK2 protein, human MeSH Browser
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.
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