Benzothiophene-based, orally active PIK3CA H1047R mutant-selective inhibitors for the treatment of HR+/HER2- breast cancer.

PI3Kα plays a key role in a variety of cellular processes, and its gene mutations are closely related to the occurrence and development of many types of cancer. Although two orthosteric PI3Kα inhibitors including Alpelisib and Inavolisib have been launched onto market, they often cause toxic and side effects due to insufficient selectivity for PIK3CA mutant protein. The development of allosteric PI3Kα inhibitors provides new ideas for overcoming these problems. Our research focuses on optimizing a novel series of allosteric PI3Kα inhibitors derived from STX-478. By integrating scaffold hopping and comprehensive structural modification strategies, we obtained the lead compound allosteric PI3Kα inhibitor 11f with a benzothiophene scaffold. The inhibitor demonstrates high selectivity for PIK3CA mutant protein, low hERG inhibition, minimal CYP inhibition, excellent in vivo efficacy, good safety and no impact on insulin balance. Collectively, these findings confirm that compound 11f is a highly promising drug candidate for the targeted therapy of PIK3CA H1047R mutant HR+/HER2-breast cancer.