Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR<sup>del19/T790M/C797S</sup> and EGFR<sup>L858R/T790M/C797S</sup>).
Fang H, Wu Y, Xiao Q, He D, Zhou T, Liu W, Yang CH, Xie Y.
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFR<sup>del19/T790M/C797S</sup> and EGFR<sup>L858R/T790M/C797S</sup> are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib. After extensive SAR studies, compound 23, the most promising candidate, exhibited strong biochemical potencies against EGFR<sup>del19/T790M/C797S</sup>, EGFR<sup>L858R/T790M/C797S</sup> and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3<sup>EGFR del19/T790M/C797S</sup> and PC-9<sup>EGFR del19/T790M/C797S</sup>. Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.