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.

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 , which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability . Subsequent optimization was performed to improve the potency and selectivity toward ATM and attenuate the hepatic clearance , culminating in the identification of with nanomolar ATM inhibition, excellent cellular sensitivity to radiation and chemotherapy drugs, and impressive pharmacokinetic profiles. Furthermore, combined with 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.