Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) RAS-binding domain Cys242 (PI3Kα RBD Cys242)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα), encoded by the PIK3CA gene, is a critical lipid kinase in the PI3K/AKT/mTOR signaling pathway, regulating cell growth, survival, and metabolism [1.3.1, 1.4.1]. The RAS-binding domain (RBD) of PI3Kα facilitates its recruitment and activation by RAS GTPases, a process frequently dysregulated in various cancers [1.1.2, 1.3.5]. Cys242 is a unique, isoform-exclusive cysteine residue located within the RBD of PI3Kα [1.1.1, 1.3.4]. Targeting Cys242 with covalent small-molecule inhibitors, such as BBO-10203 and VVD-699, selectively disrupts the protein-protein interaction between RAS and PI3Kα [1.2.3, 1.3.1]. This strategy aims to inhibit oncogenic signaling in RAS-mutant or HER2-overexpressing tumors while sparing the insulin-mediated PI3K signaling required for glucose homeostasis [1.1.2, 1.3.3]. By avoiding the inhibition of the kinase's catalytic site, these Cys242-targeted agents potentially mitigate the dose-limiting hyperglycemia associated with traditional ATP-competitive PI3Kα inhibitors [1.3.1, 1.4.1].

Other names

p110α Cys242PIK3CA Cys242PI3Kα RBD C242RAS-binding domain of PI3KαCysteine 242 of p110α

Covalent inhibition of Cys242 in the RAS-binding domain to disrupt the RAS-PI3Kα protein-protein interaction.