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

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.