Discovery of 1 H-Pyrrolo[2,3- b]pyridine Derivatives as Highly Selective, and Orally Available ATM Inhibitors with Potent In Vivo Antitumor Activity
- J Med Chem. 2025 Jul 10;68(13):13907-13934. doi: 10.1021/acs.jmedchem.5c00927.
- 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
- 2. Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu 610031, Sichuan, China.
- 3. Medical Research Center, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu 610031 Sichuan, China.
- 4. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610075 Sichuan, China.
- 5. Colorectal Cancer Center and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital of Sichuan University, Chengdu 610041, China.
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.