mutant-selective PI3K-alpha H1047R inhibitor LOXO-783

An orally bioavailable, brain penetrative, selective irriversible inhibitor of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha (phosphoinositide 3-kinase alpha; PIK3CA; PI3K p110alpha) mutant H1047R, with potential antineoplastic activity. Upon oral administration, mutant-selective PI3K-alpha H1047R inhibitor LOXO-783 selectively targets and allosterically binds to the PIK3CA mutated form PI3Ka H1047R, thereby preventing the activity of the H1047R mutant. This prevents PIK3CA H1047R-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 H1047R-mutant expressing tumor cells. By specifically targeting the PIK3CA H1047R mutation, LOXO-783 may be more efficacious and less toxic than other PI3K-alpha inhibitors that are not mutant specific. 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. LOXO-783 is able to penetrate the blood-brain-barrier (BBB).