Targeting EGFR C797S Mutations with Phosphine Oxide Pyrazole Inhibitors: Therapeutic Insights and Efficacy

The abstract discusses osimertinib, a potent EGFR tyrosine kinase inhibitor, and its resistance due to the EGFR C797S mutation, which affects a significant number of patients. The mutation hinders the binding of osimertinib, posing a challenge for drug design. Researchers have developed reversible phosphine oxide pyrazole inhibitors to combat this mutation, showcasing their high efficacy in biochemical and cellular assays.

Through structure-based design, a series of these inhibitors were created, demonstrating remarkable potency against the EGFR C797S mutation. Utilizing CRISPR-Cas 9 technology, researchers developed models to assess the inhibitors' effectiveness both in vitro and in vivo.

By adjusting the physicochemical properties, the researchers achieved favorable oral bioavailability of the EGFR C797S inhibitors, exemplified by AZ’7608. This compound was shown to inhibit signaling pathways and cell growth of mutated cell lines and offered a better safety profile for wild-type EGFR. In vivo studies revealed a significant tumor growth inhibition and an enhanced effect when combined with an anti-EGFR antibody.

Pharmacodynamic studies were conducted to understand the correlation between efficacy and target modulation, highlighting the significance of sustained inhibition of EGFR phosphorylation for anti-tumor activity.

The research provides evidence for the potential of reversible phosphine oxide pyrazole inhibitors in treating tumors with the C797S mutation, an area of significant unmet medical need, and emphasizes the necessity for continued drug discovery efforts. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.