Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) H1047R mutant (PIK3CA H1047R)

PIK3CA H1047R is a prominent oncogenic hotspot mutation located in the kinase domain (exon 21) of the p110α catalytic subunit of Phosphoinositide 3-kinase alpha (PI3Kα) [1, 6]. This specific amino acid substitution (histidine to arginine at position 1047) induces a conformational change that enhances the enzyme's recruitment to the plasma membrane and its catalytic activity, leading to constitutive activation of the PI3K/AKT/mTOR signaling pathway [5, 9]. This hyperactivation drives uncontrolled cell proliferation, survival, and metabolism, making it a key driver in various malignancies, particularly hormone receptor-positive (HR+) breast cancer, endometrial cancer, and colorectal cancer [1, 11, 16]. While pan-PI3K and isoform-selective inhibitors like alpelisib are used clinically, they often cause significant on-target toxicities, such as hyperglycemia, by inhibiting wild-type PI3Kα involved in glucose homeostasis [10, 14]. Consequently, current drug development is focused on mutant-selective and allosteric inhibitors, such as RLY-2608 and STX-478, which specifically target the H1047R mutant protein to provide a wider therapeutic window and reduced systemic side effects [3, 4, 7].

Other names

p110-alpha H1047RPI3K-alpha H1047RPIK3CA p.H1047RPhosphoinositide-3-kinase catalytic subunit alpha H1047RPIK3CA kinase domain mutant

Selective inhibition of the mutant PI3K-alpha isoform, often through allosteric binding, to block hyperactivated PI3K/AKT/mTOR signaling while sparing wild-type PI3K-alpha activity to minimize metabolic side effects [3, 4, 10].