Design of Selective PARP-1 Inhibitors and Antitumor Studies
文献类型：期刊论文
| 作者 | Zhang, Yiting4; Li, Xiangqian1,4; Liu, Fang4; Bai, Xiaoyi4; Liu, Xiaochun5; Sun, Hao4; Gao, Chenxia4; Lin, Yuxi4; Xing, Pan4; Zhu, Jiqiang2 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-05-22 |
| 页码 | 25 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c02460 |
| 通讯作者 | Shi, Dayong(shidayong@sdu.edu.cn) |
| 英文摘要 | 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. |
| WOS关键词 | DERIVATIVES ; DISCOVERY ; POTENT ; REPAIR |
| 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 |
| 语种 | 英语 |
| WOS记录号 | WOS:001229490800001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://ir.qdio.ac.cn/handle/337002/185864]  |
| 专题 | 海洋研究所_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.Pilot Natl Lab Marine Sci & Technol, Lab Marine Drugs & Biol Prod, Qingdao 266237, Peoples R China 2.Shandong Linghai Biotechnol Co Ltd, Jinan 250299, Shandong, Peoples R China 3.Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Shandong, Peoples R China 4.Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China 5.Marine Biomed Res Inst Qingdao, Qingdao 266071, 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. |
入库方式： OAI收割
来源：海洋研究所
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