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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 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.

 

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The passage you provided describes the development of a series of small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, with a focus on the class I isoform PI3Kα. This isoform is often associated with solid tumors due to gene amplification or activating mutations.

The researchers aimed to create inhibitors that not only target PI3Kα but also exhibit specificity towards mutant forms of the p110α protein, which is the catalytic subunit of PI3Kα. The goal was to develop inhibitors that can selectively degrade the mutant p110α protein and inhibit the aberrant signaling pathway associated with cancer.

The optimization process involved structure-based design, where the researchers used the knowledge of the binding site of PI3Kα to inform the development of inhibitors with isoform-specific interactions. Through this approach, they were able to create potent inhibitors that showed more than 300-fold selectivity over other Class I PI3K isoforms.

Additionally, the researchers optimized the pharmacokinetic properties of the inhibitors to ensure they have favorable exposure and efficacy in vivo. This optimization process led to the identification of a clinical candidate called GDC-0077, also known as inavolisib (32). GDC-0077 is an ATP-competitive inhibitor of PI3Kα, capable of selectively degrading the mutant p110α protein.

As of the information provided, GDC-0077 (inavolisib) has advanced to a Phase III clinical trial for the treatment of patients with PIK3CA-mutant breast cancer. This suggests that the compound has shown promising results in earlier stages of clinical evaluation and is now being further investigated for its efficacy and safety in a larger patient population.

Related Products

Cat.No. Product Name Information
S8668 Inavolisib (GDC-0077) Inavolisib (GDC-0077, RG6114, RO-7113755) is a potent selective inhibitor of PI3K alpha (PI3Kα) with an IC50 of 0.038 nM. GDC-0077 is >300-fold more selective for PI3K alpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. GDC-0077 binds to the ATP binding site of PI3K and inhibits the phosphorylation of PIP2 to PIP3.

Related Targets

PI3K