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Therefore, fourth\u2010generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS\u2010106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell\u2010free assay, LS\u2010106 potently inhibited the kinase activities of EGFR<jats:sup>19del\/T790M\/C797S<\/jats:sup> and EGFR<jats:sup>L858R\/T790M\/C797S<\/jats:sup> with IC<jats:sub>50<\/jats:sub> values of 2.4\u00a0nmol\/L and 3.1\u00a0nmol\/L, respectively, which was more potent than osimertinib. Meanwhile, LS\u2010106 exhibited comparable kinase inhibitory effect to osimertinib on EGFR<jats:sup>L858R\/T790M<\/jats:sup> and wild\u2010type EGFR. Results from cellular experiments demonstrated that LS\u2010106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR<jats:sup>19del\/T790M\/C797S<\/jats:sup> or EGFR<jats:sup>L858R\/T790M\/C797S<\/jats:sup>, and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR<jats:sup>19del\/T790M\/C797S<\/jats:sup> (named PC\u20109\u2010OR cells) using the CRISPR\/Cas9 system and found that LS\u2010106 markedly suppressed the activation of EGFR<jats:sup>19del\/T790M\/C797S<\/jats:sup> and the proliferation of PC\u20109\u2010OR cells. Moreover, cells harboring EGFR<jats:sup>19del\/T790M\/C797S<\/jats:sup> underwent remarkable apoptosis upon LS\u2010106 treatment. In vivo experiments further demonstrated that oral administration of LS\u2010106 caused significant tumor regression in a PC\u20109\u2010OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60\u00a0mg\/kg, respectively. Taken together, we identified LS\u2010106 as a novel fourth\u2010generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S\u2013triple\u2010mutant tumor models.<\/jats:p>","DOI":"10.1111\/cas.15229","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T16:27:54Z","timestamp":1638462474000},"page":"709-720","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["LS\u2010106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo"],"prefix":"10.1111","volume":"113","author":[{"given":"Yingqiang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Fudan University Shanghai China"},{"name":"Division of Antitumor Pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 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