Inavolisib (PI3K alpha inhibitor)

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

A selective PI3Kα-mutant inhibitor and degrader^1-3

1. PI3K pathway in HR+ breast cancer

The PI3K pathway is frequently dysregulated in HR+ breast cancer—promoting tumor growth, disease progression, and endocrine resistance. Dysregulation is typically caused by mutations in the genes coding for pathway enzymes, including PI3K. The PI3K family of proteins comprises a variety of isoforms, and mutations in the PI3Kα isoform gene—PIK3CA—have been implicated in HR+ breast cancer.^1,4-10

2. Inavolisib: a selective PI3Kα-mutant inhibitor and degrader

Inavolisib is an investigational small molecule designed to selectively inhibit mutant PI3Kα. In preclinical models, this molecule showed potent selective inhibition of PI3Kα and has increased potency to mutant PI3K cells over wild type. It is less sensitive for the other three PI3K isoforms. Inavolisib binds to the ATP-binding site of PI3Kα, thereby blocking phosphorylation of PIP₂ to PIP₃ and preventing downstream signaling as shown in preclinical models. Moreover, inavolisib specifically degrades the mutant form of PI3Kα, resulting in reduction of pathway activity. The biochemical features of inavolisib are designed to optimize its cellular therapeutic index through reduced off-target cytotoxicity.

Inavolisib resulted in tumor regressions and induction of apoptosis in breast cancer xenograft models

PIK3CA-mutant human breast cancer xenograft models demonstrated that the presence of inavolisib results in tumor regression, induction of apoptosis, and a reduction of pathway activity biomarkers (pAKT, pPRAS40, and pS6RP). Also, in a PIK3CA-mutant human breast cancer xenograft model, the combination of inavolisib with selective estrogen receptor degradation or CDK4/6 inhibition had synergistic antitumor activity.^1,3

ATP=adenosine triphosphate; HR=hormone receptor; pAKT=phosphorylated AKT; PI3K=phosphatidylinositol 3-kinase; PIK3CA=phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha; PIP₂=phosphatidylinositol 4,5-bisphosphate; PIP₃=phosphatidylinositol 3,4,5-trisphosphate; pPRAS40=phosphorylated proline-rich AKT substrate of 40 kDa; pS6RP=phosphorylated S6 ribosomal protein.