Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia

Signal Transduct Target Ther. 2020 Feb 26;5(1):17. doi: 10.1038/s41392-020-0112-3.


Venetoclax, an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia (AML), is tolerated well in elderly patients with AML and has good overall response rates; however, resistance remains a concern. In this study, we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples. CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc. However, downregulation of Mcl-1 is transient, which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1. Accordingly, an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax. Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects
  • Benzopyrans / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / genetics*
  • Female
  • Heterografts
  • Humans
  • Imino Furanoses / administration & dosage
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Middle Aged
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-myc / genetics
  • Sulfonamides / administration & dosage*
  • Young Adult


  • Antineoplastic Agents
  • BCL2 protein, human
  • Benzopyrans
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imino Furanoses
  • MCL1 protein, human
  • MYC protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Sulfonamides
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • venetoclax
  • voruciclib