1. Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies.
- Author
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Liu Z, Jiang K, Liu Y, Li J, Huang S, Li P, Xu L, Xu X, Hu X, Zeng X, Huang Z, Zhou Y, Li J, Long K, and Wang M
- Subjects
- Humans, Animals, Cell Line, Tumor, Mice, Drug Discovery, Apoptosis drug effects, Structure-Activity Relationship, Rats, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Male, Pyrimidines pharmacokinetics, Pyrimidines therapeutic use, Pyrimidines pharmacology, Pyrimidines chemistry, Pyrimidines chemical synthesis, Mice, Nude, Brain metabolism, Female, Blood-Brain Barrier metabolism, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects
- 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.
- Published
- 2024
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