设计、合成并评价含有 4,5,6,7-四氢噻吩并[3,2-c]吡啶的嘧啶衍生物作为有效的 EGFR 抑制剂。
Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors.
机构信息
Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
出版信息
Eur J Med Chem. 2021 Dec 15;226:113845. doi: 10.1016/j.ejmech.2021.113845. Epub 2021 Sep 11.
To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFR) for use as EGFR kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFR, with an IC value of 4.0 nM and more than 42-fold selectivity for EGFR (IC = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC value of 0.086 μΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFR.
为了解决非小细胞肺癌中表皮生长因子受体（EGFR）突变引起的耐药性问题，我们运用拼合原理，设计并合成了一系列带有 4,5,6,7-四氢噻吩并[3,2-c]吡啶侧链的氨基嘧啶衍生物（根据 AZD9291 与 EGFR 的结合模式），将其作为 EGFR 激酶抑制剂。最有前途的化合物 A12 是一种非共价结合的可逆抑制剂，对 EGFR 具有优异的激酶抑制活性，IC 值为 4.0 nM，对 EGFR 的选择性超过 42 倍（IC = 170.0 nM）。此外，化合物 A12 对 H1975 细胞表现出强烈的抗增殖活性，IC 值为 0.086 μΜ。此外，A12 有效抑制细胞迁移和促进细胞凋亡，证明了其作为 EGFR 选择性抑制剂的作用机制。
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