PI3Kα H1047R (mutant-selective inhibitor)

Class

small molecule, mutant-selective inhibitor of PI3Kα (PIK3CA) H1047R, with activity against additional PIK3CA mutations including helical-domain mutants; developed by Cogent Biosciences

Pathway

blocks PI3Kα signaling driven by activating PIK3CA mutations, one of the most common oncogenic drivers in HR+/HER2- breast cancer, shown active in H1047R- and E545K-mutant preclinical breast cancer models

PI3Kα is a lipid kinase encoded by the gene PIK3CA that transmits growth-signaling information from cell-surface growth factor receptors to downstream effectors controlling cell growth, survival, and metabolism. In many cancers, particularly hormone receptor-positive, HER2-negative breast cancer, PIK3CA acquires activating mutations that lock the enzyme into a constitutively active state, driving uncontrolled proliferation independent of normal growth signals. Blocking PI3Kα activity is therefore a rational strategy to shut down this oncogenic driver. However, PI3Kα also has an essential physiological role in normal insulin signaling in liver, muscle, and fat tissue, so inhibitors that block both mutant and normal (wild-type) enzyme tend to cause elevated blood sugar as an on-target side effect. A mutant-selective inhibitor is designed to preferentially engage the altered, cancer-driving form of the enzyme—including the common H1047R mutation and other activating mutations located in a different region of the protein—while sparing the wild-type enzyme that governs normal metabolism. This selectivity profile aims to preserve anti-tumor activity across a broader group of PIK3CA-mutant cancers while reducing the metabolic toxicity that has limited earlier, non-selective PI3Kα-targeted therapies.