Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S)

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^{del19/T790M/C797S} and EGFR^{L858R/T790M/C797S} 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^{del19/T790M/C797S}, EGFR^{L858R/T790M/C797S} and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3^{EGFR del19/T790M/C797S} and PC-9^{EGFR del19/T790M/C797S}. Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.