Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry 2023-12, Vol.38 (1), p.2155638-2155638
• Main Authors: Chen, Rui, Wang, Zhongyuan, Sima, Lijie, Cheng, Hu, Luo, Bilan, Wang, Jianta, Guo, Bing, Mao, Shunyi, Zhou, Zhixu, Peng, Jingang, Tang, Lei, Liu, Xinfu, Liao, Weike
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Antineoplastic Agents; antitumor activity; Apoptosis; Cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Proliferation; Design; Drug Design; Drug Screening Assays, Antitumor; Flow cytometry; Hematology; Hydrogen bonds; Imidazo[12-a]pyridine derivatives; Kinases; Molecular Structure; Oncology; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphorylation; PI3Kα; Pyridines - pharmacology; Research Paper; Structure-Activity Relationship; synthesis; Tumors
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2155638

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.