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Arylazopyrazole AAP 1742 Inhibits CDK s and Induces Apoptosis in Multiple Myeloma Cells via Mcl‐1 Downregulation
Author(s) -
Jorda Radek,
Navrátilová Jana,
Hušková Zlata,
Schütznerová Eva,
Cankař Petr,
Strnad Miroslav,
Kryštof Vladimír
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12330
Subject(s) - downregulation and upregulation , multiple myeloma , cyclin dependent kinase , microbiology and biotechnology , apoptosis , chemistry , cancer research , biology , cell cycle , biochemistry , immunology , gene
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 μ m ), 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.