Discovery of selective CDK9 degraders with anti-AML activity using PROTAC technology

  • Bioorg Chem. 2026 Jun 12:180:110091. doi: 10.1016/j.bioorg.2026.110091.
Qing Li  1 ,  Fuyuan Zhou  2 ,  Ding Luo  3 ,  Yan Yang  1 ,  Tingting Hou  1 ,  Junyang Chen  1 ,  Jingsong Yu  1 ,  Shilong Wu  1 ,  Mingran Xu  1 ,  Cheng Zou  1 ,  Weiwei Xue  1 ,  Liangjing Xin  4 ,  Zhi-Peng Wang  5 ,  Chao Huang  6
Affiliations
  • 1. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, PR China.
  • 2. The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.
  • 3. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 9B4, Canada.
  • 4. The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China. Electronic address: [email protected].
  • 5. College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: [email protected].
  • 6. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, PR China. Electronic address: [email protected].
PMID: 42320115 DOI: 10.1016/j.bioorg.2026.110091
Abstract

Cyclin-dependent kinase 9 (CDK9) has emerged as a pivotal therapeutic target in oncology, characterized by aberrant overexpression in both hematologic cancers and solid neoplasms. Selective CDK9 inhibition effectively disrupts transcriptional programs in tumor cells and induces Apoptosis. Herein, we describe the generation of several proteolysis targeting chimeras (PROTACs) using the CDK9 Inhibitor DRB as the core ligand. Compound D6 emerged as the most active degrader in this series, eliciting CDK9 degradation with a Dmax value of 45% in acute myeloid leukemia (AML) cells. The cellular activity of D6 was found to be 12 times higher than that of its parental inhibitor DRB, while showing no degradation activity toward Other CDK family kinases. This enhanced antiproliferative activity was primarily mediated through increased induction of Apoptosis. Furthermore, D6 suppressed tumor growth in vivo, achieving an inhibition rate of 31%, and demonstrated a favorable safety profile. Our findings indicate that D6 is a promising candidate worthy of further investigation, and that CDK9-targeted degradation is a valuable potential therapeutic option for AML.

Keywords
AML; CDK 9; DRB inhibitor; PROTAC.
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