Design of Selective PARP-1 Inhibitors and Antitumor Studies

doi:10.1021/acs.jmedchem.3c02460

	Design of Selective PARP-1 Inhibitors and Antitumor Studies
	Zhang, Yiting 1; Li, Xiangqian 1,2; Liu, Fang 1; Bai, Xiaoyi 1; Liu, Xiaochun 3; Sun, Hao 1; Gao, Chenxia 1; Lin, Yuxi 1; Xing, Pan 1; Zhu, Jiqiang 4; Liu, Ruihua 1; Wang, Zemin 1; Dai, Jiajia 5; Shi, Dayong 1,2,4
	2024-05-22
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0022-2623
页码	25
通讯作者	Shi, Dayong([email protected])
摘要	Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of alpha-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 +/- 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.
DOI	10.1021/acs.jmedchem.3c02460
收录类别	SCI
语种	英语
资助项目	National Key Research and Development Program of China[2022YFC2804105]; Natural Science Foundation of Shandong Province[ZR2023MH245]; Natural Science Foundation of Shandong Province[ZR2022QB090]; Natural Science Foundation of Shandong Province[ZR2020QH364]; Key R&D Program of Shandong Province, China[2023CXGC010413]; Qingdao Emerging Industry Cultivation Project[23-1-4-xxgg-19nsh]; Shandong Provincial Science and Technology SME Innovation Capacity Improvement Project[2022TSGC2204]; Special Research Assistant of Chinese Academy of Sciences
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:001229490800001
出版者	AMER CHEMICAL SOC
WOS关键词	DERIVATIVES ; DISCOVERY ; POTENT ; REPAIR
引用统计	被引频次：1[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/185865
专题	海洋生态与环境科学重点实验室
通讯作者	Shi, Dayong
作者单位	1.Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China 2.Pilot Natl Lab Marine Sci & Technol, Lab Marine Drugs & Biol Prod, Qingdao 266237, Peoples R China 3.Marine Biomed Res Inst Qingdao, Qingdao 266071, Peoples R China 4.Shandong Linghai Biotechnol Co Ltd, Jinan 250299, Shandong, Peoples R China 5.Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Yiting,Li, Xiangqian,Liu, Fang,et al. Design of Selective PARP-1 Inhibitors and Antitumor Studies[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:25.
APA	Zhang, Yiting.,Li, Xiangqian.,Liu, Fang.,Bai, Xiaoyi.,Liu, Xiaochun.,...&Shi, Dayong.(2024).Design of Selective PARP-1 Inhibitors and Antitumor Studies.JOURNAL OF MEDICINAL CHEMISTRY,25.
MLA	Zhang, Yiting,et al."Design of Selective PARP-1 Inhibitors and Antitumor Studies".JOURNAL OF MEDICINAL CHEMISTRY (2024):25.