Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR^T790M/C797S Mutants

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR^T790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFR^{L858R/T790M/C797S} and EGFR^{19Del/T790M/C797S} kinases with IC₅₀ values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFR^T790M/C797S mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR^T790M/C797S with a close derivative 18f was solved to provide insight on the inhibitor’s binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.