Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα

Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3K alpha is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Herein, we describe the optimization and characterization of a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3K alpha which also induce the selective degradation of the mutant p110 alpha protein, the catalytic subunit of PI3K alpha. Structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate GDC-0077 (inavolisib, 32), which is now under evaluation in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.

Automated summary

This study optimized a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3K alpha that also induce selective degradation of the mutant p110 alpha protein. Structure-based design led to potent inhibitors with over 300-fold selectivity and further optimization of pharmacokinetic properties resulted in excellent in vivo efficacy. Clinical candidate GDC-0077 (inavolisib) is now being evaluated in a Phase III clinical trial for treating patients with PIK3CA-mutant breast cancer.