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  3. Design, synthesis, and biological evaluation of novel 4,4'-bipyridine derivatives acting as CDK9-Cyclin T1 protein-protein interaction inhibitors against triple-negative breast cancer

Design, synthesis, and biological evaluation of novel 4,4'-bipyridine derivatives acting as CDK9-Cyclin T1 protein-protein interaction inhibitors against triple-negative breast cancer

  • Eur J Med Chem. 2023 Oct 6:261:115858. doi: 10.1016/j.ejmech.2023.115858.
Guiping Gao 1,  Jiayi Li 2,  Yin Cao 2,  Xudan Li 2,  Yuqing Qian 3,  Xiumei Wang 2,  Mengyu Li 2,  Yingkun Qiu 2,  Tong Wu 4,  Liqiang Wang 5,  Meijuan Fang 6
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China; Huaqiao University School of Medicine Science, Quanzhou, 362021, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China; School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, PR China.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: tongywu@gmail.com.
  • 5 Huaqiao University School of Medicine Science, Quanzhou, 362021, China. Electronic address: wlq1599@163.com.
  • 6 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: fangmj@xmu.edu.cn.
PMID: 37837671 DOI: 10.1016/j.ejmech.2023.115858
Abstract

Cyclin-dependent kinase 9 (CDK9) is directly related to tumor development in triple-negative breast Cancer (TNBC) patients. Increased CDK9 is significantly associated with poor patient prognosis, while inhibiting CDK9-Cyclin T1 protein-protein interaction has recently been demonstrated as a new approach to TNBC treatment. Herein, we synthesized a novel class of 4,4'-bipyridine derivatives as potential CDK9-Cyclin T1 PPI inhibitors against TNBC. The represented compound B19 was found to be an excellent and selective CDK9-Cyclin T1 PPI inhibitor with good potency against TNBC cell lines while exhibiting lower toxicity in normal human cell lines than the positive compound I-CDK9. Notably, compound B19 showed good pharmacokinetic properties and excellent antitumor activity against TNBC (4T1) allografts in mice with a therapeutic index of more than 42 (TGI4T1(12.5 mg/kg,i.p.) = 63.1% vs. LD50 = 537 mg/kg). Moreover, the administration of B19 in combination with the PARP Inhibitor Olaparib results in a significant increase of the antitumor activity in MDA-MB-231 cells relative to that of either single agent. To our knowledge, B19 is the first reported non-metal organic compound that acts as a selective CDK9-Cyclin T1 PPI inhibitor with in vivo antitumor activity, and it may be alone and in combination with PARP Inhibitor Olaparib for TNBC therapy.

Keywords

4,4′-Bipyridine derivatives; Antitumor activity; CDK9-Cyclin T1; PPI inhibitor; Triple-negative breast cancer (TNBC).

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