Design, Synthesis, and Antitumor Activity of Potent and Selective EGFR L858R/T790M Inhibitors and Identification of a Combination Therapy to Overcome Acquired Resistance in Models of Non-small-cell Lung Cancer

Epidermal growth factor receptor (EGFR) is one of the
most studied
drug targets for the treatment of non-small-cell lung cancer (NSCLC).
Here, we report the identification, structure optimization, and structure–activity
relationship studies of quinazoline derivatives as novel selective
EGFR L858R/T790M inhibitors. The most promising compound, 28f, exhibited strong inhibitory activity against EGFR L858R/T790M (IC50 = 3.5 nM) and greater than 368-fold selectivity over EGFR
WT (IC50 = 1290 nM), a 6.7-fold improvement over osimertinib.
Furthermore, 28f effectively inhibited downstream signaling
pathways and induced apoptosis in mutant cells. In the H1975 xenograft
in vivo model, 28f exhibited a good tumor suppressive
effect. Furthermore, the combination of 28f with the
ACK1 inhibitor dasatinib produced synergistic antiproliferative efficacy
with 28f in 28f-resistant cells and in vivo.
In conclusion,28f could become a candidate drug for the
treatment of NSCLC, and the combination of 28f and dasatinib
is expected to overcome EGFR resistance.

表皮生长因子受体（Epidermal growth factor receptor，EGFR）是目前研究最为广泛的非小细胞肺癌（non-small-cell lung cancer，NSCLC）治疗药物靶点之一。本研究报道了一类新型选择性EGFR L858R/T790M抑制剂——喹唑啉衍生物的发现、结构优化及构效关系研究。所获最优化合物28f对EGFR L858R/T790M展现出强效抑制活性（半数抑制浓度IC50 = 3.5 nM），相较于野生型EGFR的选择性高达368倍以上（野生型EGFR的IC50 = 1290 nM），其活性较奥希替尼提升6.7倍。进一步实验表明，28f可有效阻断突变细胞中的下游信号通路，并诱导细胞凋亡。在H1975异种移植体内模型中，28f呈现出良好的肿瘤抑制效果。此外，将28f与ACK1抑制剂达沙替尼联用，可在28f耐药细胞及体内模型中产生协同抗增殖活性。综上，28f有望成为非小细胞肺癌治疗的候选药物，而28f与达沙替尼的联合用药策略亦有望克服EGFR耐药性。