Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer,Archiv der Pharmazie

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Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2023-11-27 , DOI: 10.1002/ardp.202300460
Shidi Xu ₁ , Zhihui Zhou _{1,

2} , Jie He ₁ , Jiaojiao Guo ₁ , Xiaoling Huang ₁ , Yufeng An ₁ , Qingshan Pan ₁ , Shan Xu ₁ , Wufu Zhu ₁

Affiliation

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFR^T790M/C797S, several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFR^{Del19/T790M/C797S} and H1975-EGFR^L858R/T790M cells, with an IC₅₀ of 0.22 ± 0.07 and 0.52 ± 0.03 μM, respectively. Meanwhile, the kinase activity of A23 against EGFR^L858R/T790M and EGFR^{Del19/T790M/C797S} was also evaluated, with an IC₅₀ of 0.33 and 0.133 μM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFR^{Del19/T790M/C797S} inhibitor.

中文翻译：

新型生物活性2-苯基-4-氨基嘧啶衍生物作为EGFRDel19/T790M/C797S抑制剂用于治疗非小细胞肺癌

表皮生长因子受体（EGFR）的过度表达与非小细胞肺癌（NSCLC）的发展有关。因此，EGFR是治疗NSCLC的有效药物靶点，目前正在研究开发第四代EGFR抑制剂以克服T790M/C797S突变介导的耐药性。本研究基于Angew2017-7634-1与EGFR ^T790M/C797S的结合模型，设计并合成了多个系列的2-苯基-4-氨基嘧啶衍生物。评估这些化合物的生物活性，结果表明化合物A23能够有效抑制Ba/F3-EGFR ^{Del19/T790M/C797S}和H1975-EGFR ^L858R/T790M细胞的增殖，IC ₅₀分别为0.22±0.07和0.52±分别为0.03μM。同时，还评估了A23针对EGFR ^L858R/T790M和EGFR ^{Del19/T790M/C797S}的激酶活性，IC ₅₀分别为0.33和0.133 μM。此外，化合物A23在H1975异种移植模型中进一步得到了显着的体内肿瘤生长抑制作用，达到25.5%，这意味着A23可以有效抑制肿瘤细胞的生长并促进肿瘤细胞的死亡。因此， A23可以被确定为一种新型潜在的 EGFR ^{Del19/T790M/C797S}抑制剂。

更新日期：2023-11-27

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