Pan-mutant-selective PI3K-alpha Inhibitor and Degrader ETX-636

**Semantic type:** Pharmacologic Substance

**Definition:** An orally bioavailable, pan-mutant selective inhibitor and degrader of the catalytic subunit of class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) alpha (phosphoinositide 3-kinase alpha; PIK3CA; PI3K p110alpha), with potential antineoplastic activity. Upon oral administration, pan-mutant-selective PI3K-alpha inhibitor and degrader ETX-636 selectively targets and allosterically binds to PIK3CA mutated forms, thereby inhibiting the activity of PIK3CA mutants. In addition, ETX-636 induces proteasome-mediated degradation of mutant PIK3CA. Altogether, ETX-636 may prevent mutant PIK3CA-mediated activation of the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway, which may lead to both apoptosis and growth inhibition in PIK3CA mutant-expressing tumor cells. By specifically targeting PIK3CA mutants, ETX-636 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 radiotherapy. PIK3CA, one of the most frequently mutated oncogenes, encodes the p110-alpha catalytic subunit of the class I PI3K.

**Synonyms:** - ETX 636 - ETX-636 - ETX636 - Mutant-selective PI3Ka Degrader/Inhibitor ETX-636 - Mutant-selective PI3Ka Inhibitor and Degrader ETX-636 - Mutant-selective PI3Ka Inhibitor/Degrader ETX-636 - PI3K-alpha Inhibitor and Degrader ETX-636