2. Academic Validation
  3. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

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

  • Eur J Med Chem. 2021 Feb 5:211:113091. doi: 10.1016/j.ejmech.2020.113091.
Xiaqiu Qiu 1,  Yuanqing Li 2,  Bin Yu 1,  Jie Ren 1,  Huidan Huang 3,  Min Wang 1,  Hong Ding 2,  Zhiyu Li 1,  Jubo Wang 1,  Jinlei Bian 4
Affiliations

Affiliations

  • 1 State 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.
  • 2 State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 School of Pharmacy, Wannan Medical College, Wuhu, 241002, PR China. Electronic address: huanghuidan1989@163.com.
  • 4 State 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. Electronic address: bianjl@cpu.edu.cn.
PMID: 33338869 DOI: 10.1016/j.ejmech.2020.113091
Abstract

Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential Cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 Inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of Apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia.

Keywords

AML; Antitumor; CDK9; Degrader; PROTAC.

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