Definition

An orally bioavailable, pan-mutant selective inhibitor of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha (phosphoinositide 3-kinase alpha; PIK3CA; PI3K p110alpha), with potential antineoplastic activity. Upon oral administration, pan-mutant-selective PI3K-alpha inhibitor RLY-5836 selectively targets and allosterically binds to PIK3CA mutated forms, thereby preventing the activity of PIK3CA mutants. This prevents mutant PIK3CA-mediated activation of the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway. This results in both apoptosis and growth inhibition in PIK3CA mutant-expressing tumor cells. By specifically targeting PIK3CA mutants, RLY-5836 may be more efficacious and less toxic than PI3K-alpha inhibitors that also inhibit the wild-type (WT) form. Dysregulation of the PI3K/Akt/mTOR pathway is often found in solid tumors and results in the promotion of tumor cell growth, survival, and resistance to chemo- and radio-therapy. PIK3CA, one of the most frequently mutated oncogenes, encodes the p110-alpha catalytic subunit of the class I PI3K.