Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance.
Finlay MRV, Barton P, Bickerton S, Bista M, Colclough N, Cross DAE, Evans L, Floc'h N, Gregson C, Guérot CM, Hargreaves D, Kang X, Lenz EM, Li X, Liu Y, Lorthioir O, Martin MJ, McKerrecher D, McWhirter C, O'Neill D, Orme JP, Mosallanejad A, Rahi A, Smith PD, Talbot V, Ward RA, Wrigley G, Wylot M, Xue L, Yao T, Ye Y, Zhao X.
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 <b>12</b> that showed improved cell potency, oral exposure, and <i>in vivo</i> activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.