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

Abstract

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 PI3Kα 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 PI3Kα which also induce the selective degradation of the mutant p110α protein, the catalytic subunit of PI3Kα. 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.

Targeting Breast Cancer: An Overlook on Current Strategies

“…Alpelisib (NVP-BYL719, Piqray, Table 4 ) is an oral PI3Kα selective inhibitor that was approved by FDA in 2019 for PIK3CA -mutated, HR+/HER2 − advanced BC in combination with fulvestrant [ 195 ]. Other PI3K inhibitors are in clinical study, such as Inavolisib (GDC-0077), a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α [ 196 ]. It has demonstrated encouraging preliminary results in a phase I/Ib clinical study in patients with PIK3CA -mutated HR + /HER − MBC as a monotherapy, and in combination with palbociclib and/or endocrine therapy.…”

Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein

“…The high occurrence of these PI3Kα mutant proteins in solid tumors has led to the design of isoform-selective orthosteric inhibitors of PI3Kα, − including the only clinically approved inhibitor of PI3Kα, alpelisib ( 1 ). ,,, However, treatment with alpelisib commonly results in hyperglycemia within patients, a form of on-target toxicity that can result in dose interruption, reduction, or discontinuation. − This on-target toxicity is a consequence of the key role that PI3Kα WT plays in the regulation of glucose metabolism, − and results in a limited therapeutic index. For this reason, recent research in this field has focused on the discovery of compounds that selectively inhibit the mutant forms of PI3Kα (i.e., H1047X, E545X, and E542X).…”

Allosteric Inhibitors of the SARS-COV-2 Papain-like Protease Domain Induce Proteasomal Degradation of Its Parent Protein NSP3

“…More recently, monovalent degrader molecules have attracted increasing interest . Their chemical makeup ranges from UPS-targeted (with the cereblon-targeting immunomodulatory drugs being the first drugs discovered in this class − ) to target ligand-based (such as the PI3Kα degrader inavolisib). While bivalent degraders recruit known ubiquitination machinery and therefore operate through a well-defined mechanism, their physicochemical properties tend to be poor.…”