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 resistance to endocrine treatment. 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. GDC-0077: a selective PI3Kα-mutant inhibitor and degrader

GDC-0077 is an investigational small molecule designed to selectively inhibit mutant PI3Kα. This molecule is thought to be >300-fold more selective for PI3Kα over other class I PI3K isoforms, including PI3Kδ. GDC-0077 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, GDC-0077 specifically degrades the mutant form of PI3Kα, resulting in reduction of pathway activity. The biochemical features of GDC-0077 are designed to optimize its cellular therapeutic index through reduced off-target cytotoxicity.^1-3,11

GDC-0077 resulted in tumor regressions and induction of apoptosis in breast cancer xenograft models

PIK3CA-mutant human breast cancer xenograft models demonstrated that GDC-0077 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 GDC-0077 with selective estrogen receptor degradation or CDK4/6 inhibition improved antitumor activity compared with the individual modalities.^1,3

ATP=adenosine triphosphate; CDK=cyclin-dependent kinase; 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; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.