Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors.
Dou D, Wang J, Qiao Y, Wumaier G, Sha W, Li W, Mei W, Yang T, Zhang C, He H, Wang C, Chu L, Sun B, Su R, Ma X, Gong M, Xie L, Jiang W, Diao Y, Zhu L, Zhao Z, Chen Z, Xu Y, Li S, Li H.
Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFR<sup>L858R/T790M/C797S</sup> (IC<sub>50</sub> = 0.75 μM) and BaF3-EGFR<sup>19del/T790M/C797S</sup> (IC<sub>50</sub> = 0.09 μM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR<sup>19del/T790M/C797S</sup> cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR<sup>19del/T790M/C797S</sup> xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.