Discovery of 1<i>H</i>‑Pyrrolo[2,3‑<i>b</i>]pyridine Derivatives as Highly Selective, and Orally Available ATM Inhibitors with Potent In Vivo Antitumor Activity

ATM plays a critical role in maintaining genomic stability and represents a promising antitumor target. Building upon previously reported ATR/ATM dual-target inhibitor, we rationally designed a series of 1H-pyrrolo[2,3-b]pyridine derivatives as highly selective ATM inhibitors. Through systematic structural optimization, compound 25a was identified as the lead candidate, exhibiting excellent kinase selectivity (>700-fold over PIKK family members) in vitro. Notably, 25a demonstrated excellent drug-like properties with an oral bioavailability of 147.6% in mice. Mechanistically, the synergistic antitumor efficacy of 25a combined with irinotecan relied on inhibition ATM pathway. In HCT116 and SW620 xenograft models, 25a combined with irinotecan demonstrated a synergistic antitumor efficacy with TGI of 79.3% and 95.4%, respectively. These findings position 25a as a novel chemosensitizer candidate for combination therapy in solid tumors.