Definition

An orally bioavailable, covalent inhibitor of class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha (PIK3CA; PI3K p110alpha), with potential antineoplastic activity. Upon oral administration, PI3K-alpha inhibitor TOS-358 selectively targets, binds to and covalently inhibits wild-type PIK3CA and its mutated forms in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway. This results in both apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting PIK3CA, this agent may be more efficacious and less toxic than pan-PI3K inhibitors. 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.