Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation

Chem Biol Drug Des. 2014 Oct;84(4):402-8. doi: 10.1111/cbdd.12330. Epub 2014 May 12.

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.

Keywords: CAN508; cyclin-dependent kinase; inhibitor; multiple myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Azo Compounds / chemistry
  • Azo Compounds / pharmacology*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / metabolism
  • Down-Regulation / drug effects*
  • Enzyme Activation / drug effects
  • Humans
  • Mitochondria / metabolism
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • RNA Polymerase II / metabolism
  • RNA, Messenger / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • AAP1742
  • Antineoplastic Agents
  • Azo Compounds
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazoles
  • RNA, Messenger
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • pyrazole
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II