Potently inhibiting cancer cell migration with novel 3H-pyrazolo[4,3-f]quinoline boronic acid ROCK inhibitors
| Autor: | Herman O. Sintim, Neetu Dayal, Brandon Carter-Cooper, George A Naclerio, Delmis E. Hernandez, Clinton G. Mikek, Rena G. Lapidus, Elizabeth Fei Yin Chu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
Antineoplastic Agents 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Cell Movement Cell Line Tumor Drug Discovery Humans Cytotoxicity Protein Kinase Inhibitors Rho-associated protein kinase Cell Proliferation 030304 developmental biology Pharmacology chemistry.chemical_classification rho-Associated Kinases 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Kinase Organic Chemistry Autophagy Fasudil General Medicine Boronic Acids 0104 chemical sciences Enzyme chemistry Biochemistry Quinolines Drug Screening Assays Antitumor Growth inhibition Boronic acid |
| Zdroj: | European Journal of Medicinal Chemistry. 180:449-456 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2019.06.089 |
| Popis: | Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 μM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 μM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not. |
| Databáze: | OpenAIRE |
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