Transformational EGFR Drug Discovery

Since the identification of the T790M resistance mutation and WT-EGFR-driven toxicities, several newer EGFR TKIs have been developed. Osimertinib (Osi), an irreversible inhibitor that targets C797 in the EGFR active site, is currently the only widely used third-generation EGFR TKI and has inhibitory activity against the T790M resistance mutation as well as the primary, sensitizing mutations. While Osi shows clear patient benefit in first and second-line settings, acquired resistance also emerges over time. The most commonly occurring EGFR-dependent resistance mutation resulting from treatment with Osi is the C797S mutation, which disrupts covalent binding of the inhibitor, resulting in progression of the disease. A potentially transformational new medicine has been developed by  to target this particular EGFR+/T790M/C797S mutation resulting in the identification of BLU-945, a potent and selective EGFR+/T790M and EGFR+/T790M/C797S inhibitor. Using Blueprint Medicines’ proprietary compound library, compound 4 was identified with moderate EGFR mutant potency but excellent selectivity over WT-EGFR. The initial phase of optimization focused on improving potency, and a scaffold-hop to a 2,7-naphthyridine improved EGFR+/T790M and EGFR+/T790M/C797S enzymatic and cellular potency without compromising WT-EGFR selectivity. Subsequent optimization of kinome selectivity, metabolic stability, and cellular potency resulted in lead compound 27. Further analysis of 27 revealed a glucuronidation liability leading to high in vivo clearance in cyno. A strategy of mitigating glucuronidation by sterically encumbering the site of glucuronidation paired with analysis of new compounds in monkey IV PK studies for improved clearance enabled the identification of compounds with a reduced glucuronidation liability. This effort ultimately led to the identification of BLU-945. Evaluation of BLU-945 in osimertinib-resistant mouse xenograft models showed robust tumor growth inhibition. In addition to excellent in vivo tumor activity, an acceptable non-clinical safety profile supported selection as a clinical candidate. BLU-945 is currently being evaluated in a Phase 1/2 clinical trial (NCT 04862780). Really elegant drug discovery and medicinal chemistry from the Blueprint Medicines' team. Congratulations  on the first author publication - the team is very proud of you!