Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Eur J Med Chem. 2023 Dec 5;261:115865. doi: 10.1016/j.ejmech.2023.115865. Epub 2023 Oct 14.
The EGFR mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFR-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFR TK and EGFR TK with IC values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFR) and KC-0122 (BaF3-EGFR) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFR-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmR mutation.
EGFR 突变是临床使用奥希替尼治疗非小细胞肺癌（NSCLC）后获得性耐药的主要机制。迄今为止，尚无抑制剂被批准用于克服奥希替尼引起的耐药性。在这项研究中，设计、合成并评估了一系列具有苯氨基嘧啶骨架的奥希替尼衍生化合物，作为第四代表皮生长因子受体酪氨酸激酶抑制剂。结果表明，化合物 Os30 对 EGFR TK 和 EGFR TK 的抑制活性分别为 18 nM 和 113 nM。此外，Os30 能够强力抑制 KC-0116（BaF3-EGFR）和 KC-0122（BaF3-EGFR）细胞的增殖。另外，Os30 能够以浓度依赖的方式抑制 KC-0116 细胞中 EGFR 的磷酸化，将 KC-0116 细胞阻滞在 G1 期，并诱导 KC-0116 细胞凋亡。更重要的是，Os30 在 KC-0116 细胞异种移植裸鼠肿瘤模型中表现出强大的抗肿瘤疗效，在 40 mg/kg 剂量下肿瘤生长抑制率为 77.6%。这些发现表明，对奥希替尼进行修饰可以发现新的有效 EGFR-TK 抑制剂，化合物 Os30 是一种有效的第四代表皮生长因子受体酪氨酸激酶抑制剂，可用于治疗具有 EGFmR 突变的 NSCLC。
