Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance
M. Raymond V. Finlay, Peter Barton, Sue Bickerton, Michał Biśta, Nicola Colclough, Darren A.E. Cross, Laura Evans, Nicolas Floc’h, Clare Gregson, Carine Guérot, David Hargreaves, Xiaoming Kang, Eva M. Lenz, Xu Li, Yi Liu, Olivier Lorthioir, Matthew J. Martin, Darren McKerrecher, Claire McWhirter, Daniel O’Neill, Jonathan P. Orme, Arash Mosallanejad, Amar Rahi, Paul D. Smith, Verity Talbot, Richard A. Ward, Gail L. Wrigley, Marta Wylot, Lin Xue, Tieguang Yao, Ye Yang, Xiliang Zhao
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.