2. Academic Validation
  3. Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities

Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities

  • Eur J Med Chem. 2023 Nov 5;259:115709. doi: 10.1016/j.ejmech.2023.115709.
Pingyuan Wang 1,  Wen-Ting Zhu 2,  Yajing Wang 3,  Shan-Shan Song 2,  Yong Xi 2,  Xin-Ying Yang 2,  Yan-Yan Shen 2,  Yi Su 2,  Yi-Ming Sun 2,  Ying-Lei Gao 2,  Yi Chen 2,  Jian Ding 2,  Ze-Hong Miao 2,  Ao Zhang 4,  Jin-Xue He 5
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Key Laboratory of Evolution and Marine Biodiversity Ministry of Education, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China. Electronic address: wangpingyuan@ouc.edu.cn.
  • 2 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 3 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 4 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 5 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: jinxue_he@simm.ac.cn.
PMID: 37567056 DOI: 10.1016/j.ejmech.2023.115709
Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient Cancer cells and elicit Anticancer effect through a mechanism of synthetic lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3-a]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m, 19a, 19c, 19e, 19i and 19k not only displayed more potent inhibitory activities (IC50s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1-/-, IC50s < 1.9 nM) and Capan-1 (BRCA2-/-, IC50s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC50s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance.

Keywords

Anticancer; Drug resistance; PARP1 inhibitor; Structure−activity relationship; Synthetic lethality.

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