Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation
| Autor: | Radek Jorda, Jana Navrátilová, Zlata Huskova, Vladimír Kryštof, Eva Schütznerová, Miroslav Strnad, Petr Cankař |
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| Rok vydání: | 2014 |
| Předmět: |
Down-Regulation
RNA polymerase II Antineoplastic Agents Apoptosis X-Linked Inhibitor of Apoptosis Protein Biology Biochemistry Downregulation and upregulation Cyclin-dependent kinase Cell Line Tumor Drug Discovery Humans RNA Messenger Phosphorylation Pharmacology Kinase Organic Chemistry Cyclin-Dependent Kinase 9 Cell biology XIAP Mitochondria Enzyme Activation Proto-Oncogene Proteins c-bcl-2 Cell culture biology.protein Cancer research Molecular Medicine Myeloid Cell Leukemia Sequence 1 Protein Pyrazoles RNA Polymerase II Multiple Myeloma Azo Compounds |
| Zdroj: | Chemical biologydrug design. 84(4) |
| ISSN: | 1747-0285 |
| Popis: | Inhibitors of cyclin-dependent kinases 9 have been developed as potential anticancer drugs for the treatment of multiple myeloma. We have previously prepared a library of arylazo-3,5-diaminopyrazole inhibitors of CDKs. Here, we describe a novel member, AAP1742 (CDK9 inhibition with IC(50) = 0.28 μm), that reduces the viability of multiple myeloma cell lines in low micromolar concentrations. Consistent with inhibition of CDK9, AAP1742 decreases the phosphorylation of RNA polymerase II and inhibits mRNA synthesis of anti-apoptotic proteins Mcl-1, Bcl-2, and XIAP, followed by apoptosis in the RPMI-8226 cell line in a dose- and a time-dependent manner. These results are consistent with the biochemical profile of AAP1742 and further suggest cellular inhibition of CDK9 as a possible target for anticancer drugs. |
| Databáze: | OpenAIRE |
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