Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) H1047X mutant (PI3Kα H1047X)

PI3Kα H1047X mutants refer to oncogenic variations in the catalytic subunit (p110α) of the Phosphatidylinositol 3-kinase alpha enzyme, specifically at the histidine 1047 residue within the kinase domain [1]. These mutations, most commonly H1047R, result in constitutive activation of the PI3K/AKT/mTOR signaling pathway, driving uncontrolled cell growth, survival, and metabolism [3]. They are among the most frequent somatic mutations in human cancers, particularly in breast, colorectal, and endometrial malignancies [2]. Therapeutic strategies involve small-molecule inhibitors like alpelisib and inavolisib that bind to the p110α subunit to block its lipid kinase activity [2, 4]. Recent drug development has focused on mutant-selective inhibitors like RLY-2608 to improve the therapeutic index and reduce systemic side effects like hyperglycemia, which is common with wild-type PI3Kα inhibition [5]. Sources: [1] UniProt (P42336) [2] André F, et al. N Engl J Med. 2019 (PMID: 31092102) [3] Burke JE. Annu Rev Biochem. 2018 (PMID: 30333116) [4] FDA Approval: Inavolisib (Oct 2024) [5] Relay Therapeutics: RLY-2608 Clinical Data

Other names

PIK3CA H1047RPIK3CA H1047LPIK3CA H1047Yp110α H1047XPhosphoinositide-3-kinase catalytic subunit alpha H1047X

Inhibition of the PI3Kα catalytic subunit to block the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby suppressing the PI3K/AKT/mTOR signaling pathway [1, 3].