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Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies

文献类型：期刊论文

作者Liu, Zhi5,6; Jiang, Kailong6; Liu, Yan4,5,6; Li, Junfei3,6; Huang, Siqi6; Li, Ping6; Xu, Lei6; Xu, Xiaomin6; Hu, Xiaobei2,6; Zeng, Xia6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-25
卷号67期号:15页码:12735-12759
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00734
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Long, Kai(longkai@annovabiotech.com) ; Wang, Mingliang(wangmingliang@simm.ac.cn)
英文摘要The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood-brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.
WOS关键词DNA-DAMAGE RESPONSE ; CANCER-CELLS ; REPLICATIVE STRESS ; DESIGN ; KINASE
资助项目Shanghai Annova Biotechnology Co., Ltd. ; Guangdong High-level New RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003] ; Creative Research Group of Zhongshan City (Lingnan Pharmaceutical Research and Innovation team)[CXTD2022011] ; National Natural Science Foundation of China[82304539] ; Shanghai Special Fund for Talent Development (Shanghai Super Postdoctoral Incentive Program)[2022690] ; China Postdoctoral Science Foundation[2023M733629]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001279661600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312535]  
专题中国科学院上海药物研究所
通讯作者Zhou, Yubo; Li, Jia; Long, Kai; Wang, Mingliang
作者单位1.Shanghai Annova Biotechnol Co Ltd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Zhi,Jiang, Kailong,Liu, Yan,et al. Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(15):12735-12759.
APA Liu, Zhi.,Jiang, Kailong.,Liu, Yan.,Li, Junfei.,Huang, Siqi.,...&Wang, Mingliang.(2024).Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies.JOURNAL OF MEDICINAL CHEMISTRY,67(15),12735-12759.
MLA Liu, Zhi,et al."Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies".JOURNAL OF MEDICINAL CHEMISTRY 67.15(2024):12735-12759.

入库方式： OAI收割

来源：上海药物研究所

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