2. Academic Validation
  3. Design, synthesis and anticancer evaluation of selective 2,4-disubstituted pyrimidine CDK9 inhibitors

Design, synthesis and anticancer evaluation of selective 2,4-disubstituted pyrimidine CDK9 inhibitors

  • Eur J Med Chem. 2022 Dec 15;244:114875. doi: 10.1016/j.ejmech.2022.114875.
Zichen Xu 1,  Bin Zhang 2,  Zhikun Liu 1,  Shaohua Gou 3
Affiliations

Affiliations

  • 1 Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, Chinas.
  • 2 Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, Chinas; School of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian, 463000, China.
  • 3 Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, Chinas. Electronic address: sgou@seu.edu.cn.
PMID: 36332552 DOI: 10.1016/j.ejmech.2022.114875
Abstract

Specific inhibition on CDK9 has been proven to be a promising targeted Cancer therapy. In this work, fourteen novel 2,4-disubstituted pyrimidine derivatives were designed and synthesized as potent and selective CDK9 inhibitors. These compounds showed broad anti-proliferative activities in various tumor cell lines, especially for PANC-1 cells with IC50 values as low as 0.08 μM. The most selective compound 8d was 84-fold selective for CDK9 over CDK2. Mechanism study indicated that 8d induced Apoptosis of PANC-1 cells and arrested the cell cycle at G2/M phase in a dose-dependent manner. Decreased phosphorylation of the CTD of RNAPII at Ser-2 and downregulation of CDK9 were confirmed in PANC-1 cells. Besides, Molecular docking was also performed to gain insights into the ligand-binding interactions of 8d inside CDK9 and CDK2 binding sites. In vivo studies indicated that 8d exhibited potent anti-tumor effects in PANC-1 xenograft models without causing obvious loss of body weight. Our research suggests that compound 8d, as a potent CDK9 Inhibitor, can be considered as a good lead-candidate for further development.

Keywords

2,4-Disubstituted pyrimidine; Anticancer; CDK9 inhibitor; Pancreatic cancer; Selective kinase inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151984
    CDK9 Inhibitor
    CDK