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

文献类型：期刊论文

作者Wang, Pingyuan1,3; Zhu, Wen-Ting2,4; Wang, Yajing1; Song, Shan-Shan2,4; Xi, Yong2,4; Yang, Xin-Ying2,4; Shen, Yan-Yan2,4; Su, Yi2,4; Sun, Yi-Ming2,4; Gao, Ying-Lei2,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-11-05
卷号259页码:19
ISSN号0223-5234
关键词PARP1 inhibitor Synthetic lethality Drug resistance Anticancer Structure -activity relationship
DOI10.1016/j.ejmech.2023.115709
通讯作者Wang, Pingyuan(wangpingyuan@ouc.edu.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要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 (IC(50)s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1(-/-), IC(50)s < 1.9 nM) and Capan-1 (BRCA2(-/-), IC(50)s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC(50)s < 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.
WOS关键词BIOLOGICAL EVALUATION ; POLY(ADP-RIBOSE) POLYMERASE-1 ; IV INHIBITOR ; DUAL PARP ; DERIVATIVES ; DESIGN ; REPAIR ; POTENT ; TUMORS ; CELLS
资助项目National Natural Science Foundation of China[82273767] ; National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[82073865] ; Science and Technology Commission of Shanghai Municipality (Shanghai Rising-Star Program)[19QA1410900] ; State Key Laboratory of Drug Research ; Taishan Scholars Program of Shandong Province[tsqn202211060]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001062805100001
源URL[http://119.78.100.183/handle/2S10ELR8/306134]  
专题新药研究国家重点实验室
通讯作者Wang, Pingyuan; He, Jin-Xue
作者单位1.Shanghai Jiao Tong Univ, Coll Pharmaceut Sci, Shanghai Frontiers Sci Ctr Drug Target Identificat, Shanghai 200240, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
3.Ocean Univ China, Inst Evolut & Marine Biodivers, Key Lab Evolut & Marine Biodivers, Minist Educ, Qingdao 266003, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Jinan 201203, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Pingyuan,Zhu, Wen-Ting,Wang, Yajing,et al. Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,259:19.
APA Wang, Pingyuan.,Zhu, Wen-Ting.,Wang, Yajing.,Song, Shan-Shan.,Xi, Yong.,...&He, Jin-Xue.(2023).Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,259,19.
MLA Wang, Pingyuan,et al."Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 259(2023):19.

入库方式： OAI收割

来源：上海药物研究所

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