TOS-358

**TOS-358** is a first-in-class, highly specific covalent inhibitor of phosphoinositide 3‑kinase alpha (PI3Kα), developed by Totus Medicines for the treatment of solid tumors harboring PIK3CA mutations. It is an orally administered small molecule designed to selectively and irreversibly bind to both wild-type and mutant forms of the PIK3CA enzyme, a key component in the PI3K/Akt/mTOR signaling pathway that drives tumor growth and survival in many cancers. By forming a covalent bond with its target, TOS-358 achieves near-complete (up to 95–100%) inhibition of PI3Kα activity, resulting in apoptosis and growth inhibition specifically in PIK3CA-expressing tumor cells. Unlike previous reversible inhibitors, which are limited by off-target effects and dose-limiting toxicities such as hyperglycemia, TOS-358 demonstrates superior specificity with minimal off-target toxicity at efficacious doses. Early clinical trials have shown promising results with high target engagement, initial clinical activity (including unconfirmed complete responses), no grade 3/4 toxicities at low doses, and several patients remaining progression-free for over six months. The drug is currently being evaluated in phase 1b expansion studies across multiple cancer types including breast cancer (hormone receptor positive), endometrial cancer, urothelial carcinoma, head & neck cancers—specifically those expressing PI3K-alpha mutations[1][2][4][5][6][7].