Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China.
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China.
Bioorg Med Chem Lett. 2023 Jul 15;91:129381. doi: 10.1016/j.bmcl.2023.129381. Epub 2023 Jun 17.
The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFR mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR. Based on these results, A5 turned out to be effective reversible EGFR-TKIs which can be further developed.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）在非小细胞肺癌治疗中的临床应用受到 EGFR 突变引起的耐药性限制。因此，为了克服耐药性，我们设计并合成了一系列 2-氨基嘧啶衍生物作为 EGFR-TKIs。在这些化合物中，化合物 A5 和 A13 对 KC-0116（EGFR）细胞系表现出显著的抗增殖活性和高选择性。A5 抑制 EGFR 磷酸化并诱导 KC-0116 细胞凋亡，将 KC-0116 细胞阻滞在 G2/M 期。分子对接结果表明，A5 和布加替尼以类似的模式与 EGFR 结合。除了与 Met793 残基形成两个重要氢键外，A5 还与 Lys745 残基形成氢键，这可能对 EGFR 的强效抑制活性起重要作用。基于这些结果，A5 被证明是有效的可逆 EGFR-TKIs，可以进一步开发。
