College of Pharmacy, Dalian Medical University, Dalian, 116044, PR China.
School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Eur J Med Chem. 2021 Nov 5;223:113626. doi: 10.1016/j.ejmech.2021.113626. Epub 2021 Jun 16.
A series of diphenylpyrimidine derivatives bearing a hydroxamic acid group was designed and synthesized as noncovalent EGFR inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFR binding with ATP and suppressed the proliferation of H1975 cells with IC values of 1.097 nM and 0.09777 μM, respectively. Moreover, compound 9d also not only exhibited a high selective index of 43.4 for EGFR over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC > 20 μΜ). In addition, the action mechanism validated that compound 9d effectively inhibited cell migration and promoted cell apoptosis by blocking cell cycle at G/M stage. Furthermore, the target dose-dependently downregulated the expression of p-EGFR and arrested the activation of downstream Akt and ERK in H1975. All these studies provide important clues for the discovery of potent noncovalent EGFR inhibitors.
设计并合成了一系列含羟肟酸基团的二苯嘧啶衍生物作为非共价 EGFR 抑制剂，以提高生物活性和选择性。其中最有前途的化合物 9d 有效地干扰了 EGFR 与 ATP 的结合，并以 IC 值分别为 1.097 nM 和 0.09777 μM 的方式抑制了 H1975 细胞的增殖。此外，化合物 9d 对野生型 EGFR 的选择性指数高达 43.4，对 A431 细胞的选择性指数高达 10.9，对正常 HBE 细胞的毒性较低（IC > 20 μM）。此外，作用机制验证了化合物 9d 通过阻断细胞周期在 G/M 期有效抑制细胞迁移并促进细胞凋亡。此外，该化合物还可剂量依赖性地下调 H1975 中 p-EGFR 的表达并阻断下游 Akt 和 ERK 的激活。所有这些研究为发现有效的非共价 EGFR 抑制剂提供了重要线索。
