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Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

Xiaqiu Qiu1, Yuanqing Li2, Bin Yu1

  • 1State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

European Journal of Medicinal Chemistry
|December 18, 2020
PubMed

Insights

New PROTACs targeting Cyclin-dependent kinase 9 (CDK9) effectively degrade the protein in acute myeloid leukemia cells. The lead compound B03 shows potent anti-cancer activity and CDK9 degradation in vivo, suggesting a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase 9 (CDK9) is a key target for cancer therapy.
  • Developing selective CDK9 inhibitors is challenging due to similar ATP-binding sites among CDKs.

Purpose of the Study:

  • To develop novel proteolysis targeting chimeras (PROTACs) for targeted CDK9 degradation.
  • To evaluate the efficacy of CDK9-degrading PROTACs in acute myeloid leukemia (AML) models.

Main Methods:

  • Chemical modification of a known CDK9 inhibitor (BAY-1143572) into PROTACs.
  • Assessment of CDK9 degradation in AML cell lines.
  • Evaluation of antiproliferative activity and apoptosis induction.
  • In vivo studies to confirm CDK9 degradation.

Main Results:

  • Several PROTACs induced CDK9 degradation in AML cells at nanomolar concentrations.
  • The lead PROTAC, B03, demonstrated superior cell growth inhibition compared to the inhibitor alone.
  • B03 exhibited minimal off-target kinase inhibition and induced apoptosis.
  • CDK9 degradation was confirmed in vivo by B03.

Conclusions:

  • CDK9 degradation via PROTACs is a viable therapeutic strategy for AML.
  • B03 is a promising lead compound for further development in AML treatment.
Keywords:
AMLAntitumorCDK9DegraderPROTAC

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