2. Academic Validation
  3. Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer

Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer

  • Eur J Med Chem. 2023 Nov 5;259:115648. doi: 10.1016/j.ejmech.2023.115648.
Lan Zhang 1,  Yongqi Zhen 2,  Lu Feng 3,  Zhijia Li 4,  Yingying Lu 4,  Guan Wang 5,  Liang Ouyang 6
Affiliations

Affiliations

  • 1 Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address: zhanglanx_9@126.com.
  • 2 Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China; Department of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China.
  • 4 Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
  • 5 Department of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China. Electronic address: guan8079@163.com.
  • 6 Department of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu, 610041, China. Electronic address: ouyangliang@scu.edu.cn.
PMID: 37478560 DOI: 10.1016/j.ejmech.2023.115648
Abstract

Triple negative breast Cancer (TNBC) is one of the most aggressive breast tumors, with a high rate of recurrence and metastasis as well as a poor prognosis. Consequently, it is urgent to find new targeted therapeutic strategies and development of corresponding drugs. Previous studies have shown that CDK12 inhibitors in combination with PARP1 inhibitors is able to induce synthetic lethality in TNBC cells. Here, we reported simultaneously inhibition of CDK12 and PARP1 by genetic or pharmacological approaches synergistically inhibited the proliferation of TNBC cells. Then, a series of small molecule inhibitors targeting both CDK12 and PARP1 were designed and synthesized. The new dual-target inhibitor (12e) showed potent inhibitory activity against CDK12 (IC50 = 285 nM) and PARP1 (IC50 = 34 nM), as well as good anti-proliferative effects in TNBC cell lines. Meanwhile, compound 12e showed favorable synergistic anti-tumor efficacy in cells and xenografts by inhibiting DNA damage repair, promoting cell cycle arrest and Apoptosis. Taken together, we successfully synthesized the first effective CDK12-PARP1 dual inhibitor, which is expected to be an attractive therapeutic strategy for TNBC.

Keywords

CDK12; Dual-target inhibitor; PARP1; Synthetic lethality; TNBC.

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