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Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy

文献类型：期刊论文

作者He, Qiaolin1,2; He, Jing1,3; Huan, Xiajuan3; Song, Shanshan3; Zhang, Xiaofei1,2; He, Qian2; Miao, Zehong1,3; He, Jinxue1,3; Yang, Chunhao1,2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2026-04-05
卷号307页码:16
关键词PARP1 inhibitor Subtype selectivity Synthetic lethality In vitro cytotoxicity
ISSN号0223-5234
DOI10.1016/j.ejmech.2026.118650
英文摘要Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-b]pyridazin-2(1H)-one scaffold selectively targeting PARP1. Among these compounds, YCH3971 exhibited potent inhibiting activity against PARP1 with an IC50 of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (>1000-fold). Also, YCH3971 possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC50 of 2.10 nM. However, since the oral bioavailability of YCH3971 in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.
WOS关键词POLY(ADP-RIBOSE) POLYMERASE PARP ; DNA-REPAIR
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; National Natural Science Foundation of China[82073875] ; State Key Laboratory of Drug Research[SKLDR-2022-LH-07]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001691520600001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/323053]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者He, Jinxue; Yang, Chunhao
作者单位1.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 He, Qiaolin,He, Jing,Huan, Xiajuan,et al. Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2026,307:16.
APA He, Qiaolin.,He, Jing.,Huan, Xiajuan.,Song, Shanshan.,Zhang, Xiaofei.,...&Yang, Chunhao.(2026).Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,307,16.
MLA He, Qiaolin,et al."Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 307(2026):16.

入库方式： OAI收割

来源：上海药物研究所

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