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Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2014 Oct; Vol. 84 (4), pp. 402-8. Date of Electronic Publication: 2014 May 12. - Publication Year :
- 2014
-
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.<br /> (© 2014 John Wiley & Sons A/S.)
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Azo Compounds chemistry
Cell Line, Tumor
Cyclin-Dependent Kinase 9 metabolism
Enzyme Activation drug effects
Humans
Mitochondria metabolism
Multiple Myeloma metabolism
Multiple Myeloma pathology
Myeloid Cell Leukemia Sequence 1 Protein genetics
Phosphorylation drug effects
Proto-Oncogene Proteins c-bcl-2 genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
RNA Polymerase II metabolism
RNA, Messenger metabolism
X-Linked Inhibitor of Apoptosis Protein genetics
X-Linked Inhibitor of Apoptosis Protein metabolism
Apoptosis drug effects
Azo Compounds pharmacology
Cyclin-Dependent Kinase 9 antagonists & inhibitors
Down-Regulation drug effects
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Pyrazoles chemistry
Pyrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 84
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 24803299
- Full Text :
- https://doi.org/10.1111/cbdd.12330