Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance PMID: 34491761

ADC Targets in Oncology

2026-04-10

Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

J Med Chem. 2021 Sep 23;64(18):13704-13718. doi: 10.1021/acs.jmedchem.1c01055.

M Raymond V Finlay ¹ , Peter Barton ¹ , Sue Bickerton ¹ , Michal Bista ² , Nicola Colclough ¹ , Darren A E Cross ¹ , Laura Evans ¹ , Nicolas Floc'h ¹ , Clare Gregson ¹ , Carine M Guérot ¹ , David Hargreaves ² , Xiaoming Kang ³ , Eva M Lenz ¹ , Xu Li ³ , Yi Liu ³ , Olivier Lorthioir ¹ , Matthew J Martin ¹ , Darren McKerrecher ¹ , Claire McWhirter ² , Daniel O'Neill ² , Jonathan P Orme ² , Arash Mosallanejad ¹ , Amar Rahi ¹ , Paul D Smith ¹ , Verity Talbot ² , Richard A Ward ¹ , Gail Wrigley ¹ , Marta Wylot ¹ , Lin Xue ³ , Tieguang Yao ³ , Yang Ye ³ , Xiliang Zhao ³

Affiliations

Abstract

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung Cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR Inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.