Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24803299
DOI
10.1111/cbdd.12330
Knihovny.cz E-resources
- Keywords
- CAN508, cyclin-dependent kinase, inhibitor, multiple myeloma,
- MeSH
- Enzyme Activation drug effects MeSH
- Apoptosis drug effects MeSH
- Azo Compounds chemistry pharmacology MeSH
- Cyclin-Dependent Kinase 9 antagonists & inhibitors metabolism MeSH
- Down-Regulation drug effects MeSH
- Phosphorylation drug effects MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- Mitochondria metabolism MeSH
- Multiple Myeloma metabolism pathology MeSH
- Cell Line, Tumor MeSH
- Myeloid Cell Leukemia Sequence 1 Protein genetics metabolism MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Proto-Oncogene Proteins c-bcl-2 genetics metabolism MeSH
- Pyrazoles chemistry pharmacology MeSH
- RNA Polymerase II metabolism MeSH
- X-Linked Inhibitor of Apoptosis Protein genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- AAP1742 MeSH Browser
- Azo Compounds MeSH
- Cyclin-Dependent Kinase 9 MeSH
- MCL1 protein, human MeSH Browser
- RNA, Messenger MeSH
- Myeloid Cell Leukemia Sequence 1 Protein MeSH
- Antineoplastic Agents MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- pyrazole MeSH Browser
- Pyrazoles MeSH
- RNA Polymerase II MeSH
- X-Linked Inhibitor of Apoptosis Protein MeSH
- XIAP protein, human MeSH Browser
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.
References provided by Crossref.org
Modification of Boc-Protected CAN508 via Acylation and Suzuki-Miyaura Coupling
