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

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

  • J Med Chem. 2024 Aug 8;67(15):12735-12759. doi: 10.1021/acs.jmedchem.4c00734.
Zhi Liu 1 2,  Kailong Jiang 1,  Yan Liu 1 2 3,  Junfei Li 1 4,  Siqi Huang 1,  Ping Li 1,  Lei Xu 1,  Xiaomin Xu 1,  Xiaobei Hu 1 5,  Xia Zeng 1,  Zehui Huang 1,  Yubo Zhou 1 5,  Jia Li 1 4 5,  Kai Long 6,  Mingliang Wang 1 2 3
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 5 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 Shanghai Annova Biotechnology Co., Ltd., Shanghai 201203, China.
PMID: 39053006 DOI: 10.1021/acs.jmedchem.4c00734
Abstract

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.

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