Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha H1047R (PI3Kα H1047R)

PI3Kα H1047R is a common hotspot somatic mutation in the PIK3CA gene, which encodes the p110α catalytic subunit of Class IA phosphoinositide 3-kinase (PI3K) [1, 2]. This mutation occurs in the kinase domain and leads to constitutive activation of the PI3K/AKT/mTOR signaling pathway, driving uncontrolled cell growth, survival, and metabolism [3, 15]. It is highly prevalent in various solid tumors, particularly hormone receptor-positive (HR+) breast cancer, where it is found in approximately 20-30% of cases [7, 13]. While pan-PI3K and isoform-selective inhibitors like alpelisib are used clinically, they often cause significant side effects such as hyperglycemia due to the inhibition of wild-type PI3Kα, which is essential for glucose homeostasis [3, 10, 14]. Consequently, current drug development is focused on mutant-selective inhibitors that specifically target the H1047R variant to improve the therapeutic index and reduce systemic toxicity [4, 14]. These next-generation agents, such as RLY-2608 and STX-478, aim to provide more potent and durable responses by allowing for higher dosing without the dose-limiting metabolic toxicities associated with wild-type inhibition [14].

Other names

PIK3CA H1047Rp110α H1047Rp110-alpha H1047RPhosphoinositide 3-kinase alpha H1047RPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha H1047R

PI3K inhibitor, Mutant-selective PI3Kα inhibitor, ATP-competitive inhibitor