title: Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation.
abstract: 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.
authors.affiliation: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR and Palacký University, Šlechtitelů 11, 783 71, Olomouc, Czech Republic; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Žlutý kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.forename: Jana
authors.initials: J
authors.lastname: Navrátilová
authors.forename: Zlata
authors.initials: Z
authors.lastname: Hušková
authors.forename: Eva
authors.initials: E
authors.lastname: Schütznerová
authors.forename: Petr
authors.initials: P
authors.lastname: Cankař
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000597995:AAP1742; D000970:Antineoplastic Agents; D001391:Azo Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C031280:pyrazole; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II
keywords: CAN508; cyclin-dependent kinase; inhibitor; multiple myeloma