Discovery and Evaluation of 3-Quinoxalin Urea Derivatives as Potent, Selective, and Orally Available ATM Inhibitors Combined with Chemotherapy for the Treatment of Cancer via Goal-Oriented Molecule Generation and Virtual Screening.

ABSTRACT

ATM plays an important role in DNA damage response and is considered a potential target in cancer therapies. In this study, a goal-directed molecular generation approach based on ligand similarity and target specificity was applied to sample active molecules, and they were screened virtually to identify the theoretical lead compound 7a, which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability in vitro. Subsequent optimization was performed to improve the potency and selectivity toward ATM and attenuate the hepatic clearance in vitro, culminating in the identification of 10r with nanomolar ATM inhibition, excellent cellular sensitivity to radiation and chemotherapy drugs, and impressive pharmacokinetic profiles. Furthermore, 10r combined with irinotecan demonstrated a synergistic antitumor efficacy in SW620 xenograft models, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer.