AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Clin Cancer Res. 2020 Feb 15;26(4):922-934. doi: 10.1158/1078-0432.CCR-19-1853. Epub 2019 Nov 7.


Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573.

Experimental design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line- and patient-derived xenograft models in vivo. Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/effect relationship.

Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro, and MCL-1 depletion in a dose- and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo, which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design.

Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1-dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies ( identifier: NCT03263637).See related commentary by Alcon et al., p. 761.

Publication types

  • Comment

MeSH terms

  • Antineoplastic Agents*
  • Apoptosis / drug effects
  • Cyclin-Dependent Kinase 9
  • Hematologic Neoplasms*
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proteomics


  • Antineoplastic Agents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9

Associated data