Arylazopyrazole AAP1742 Inhibits CDKs and Induces Apoptosis in Multiple Myeloma Cells via Mcl-1 Downregulation

0433741 - ÚEB 2015 RIV GB eng J - Journal Article
Jorda, Radek - Navrátilová, Jana - Hušková, Zlata - Schütznerová, E. - Cankař, P. - Strnad, Miroslav - Kryštof, Vladimír
Arylazopyrazole AAP1742 Inhibits CDKs and Induces Apoptosis in Multiple Myeloma Cells via Mcl-1 Downregulation.
Chemical Biology & Drug Design. Roč. 84, č. 4 (2014), s. 402-408. ISSN 1747-0277. E-ISSN 1747-0285
R&D Projects: GA ČR GAP305/12/0783; GA ČR GA14-19590S; GA MŠMT(CZ) LO1204
Institutional support: RVO:61389030
Keywords : CAN508 * cyclin-dependent kinase * inhibitor
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 2.485, year: 2014
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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 IC50 =0.28mum), 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.
Permanent Link: http://hdl.handle.net/11104/0237916