发现并优化针对肺癌治疗的表皮生长因子受体（EGFR）L858R/T790M/C797S 耐药突变的强效抑制剂。
Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.
机构信息
School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
出版信息
Eur J Med Chem. 2022 Jul 5;237:114381. doi: 10.1016/j.ejmech.2022.114381. Epub 2022 Apr 15.
The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung cancer (NSCLC). In this study, we identified a potent and oral EGFR tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFR mutant with IC value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFR and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics.
EGFR 中的 C797S 突变是导致非小细胞肺癌（NSCLC）对奥希替尼获得性耐药的主要机制。在这项研究中，我们鉴定了一种新型化学骨架的有效的、口服的 EGFR 酪氨酸激酶抑制剂 14aj。化合物 14aj 对 EGFR 突变体具有低纳摩尔的活性，IC 值为 0.010 μM。体外实验表明，化合物 14aj 对携带 EGFR 的 NSCLC 细胞具有高活性，并诱导肿瘤细胞周期停滞和细胞凋亡。14aj 抑制 EGFR 的细胞磷酸化。在体内异种移植小鼠模型中，化合物 14aj 的口服给药导致显著的肿瘤消退，而没有明显的毒性。此外，该化合物具有良好的药代动力学特性。
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