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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Discovery of novel 9-heterocyclyl substituted 9H-purines as L858R/T790M/C797S mutant EGFR tyrosine kinase inhibitors
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Discovery of novel 9-heterocyclyl substituted 9H-purines as L858R/T790M/C797S mutant EGFR tyrosine kinase inhibitors

机译：发现新型9-杂环基取代的9H-嘌呤，为L858R / T790M / C797S突变型EGFR酪氨酸激酶抑制剂

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摘要

Targeting L858R/T790M/C797S mutant EGFR is a major challenge in the new-generation EGFR tyrosine kinase inhibitors development for conquering drug resistant NSCLC. In this study, a series of novel 9-heterocyclyl substituted 9H-purine derivatives were designed as EGFR(L858 R/T790 M/C797S) tyrosine kinase inhibitors. Among these compounds, D4, D9, D11 and D12 showed significantly potent anti-proliferation and EGFR(L858 R/T790 M/C797S) inhibition activity. In particular, the most potent compound D9 showed anti-proliferation against HCC827 and H1975 cell lines with the IC50 values of 0.00088 and 0.20 mu M, respectively. And D9 inhibited the EGFR(L858 R/T790 M/C797S )with an IC50 value of 18 nM. Furtherly, D9 could significantly suppress the EGFR phosphorylation, induce the apoptosis, arrest cell cycle at G0/G1, and inhibit colony formation in HCC827 cell line by a concentration-dependent manner. Molecular docking indicated that the introduction of a cyclopropylsulfonamide group in D9 led to the formation of additional two hydrogen bonds with mutant Ser797 which played key roles in generating efficient EGFR(L858 R/T790 M/C797S) inhibitory activity. These findings strongly indicated that 9-heterocyclyl substituted 9H-purine derivatives were promising L858R/T790M/C797S mutant EGFR-TKIs. The introduction of extra hydrogen bond interaction with mutant Ser797 is efficient method for the design of the fourth-generation EGFR-TKIs. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：靶向L858R / T790M / C797S突变体EGFR是新一代EGFR酪氨酸激酶抑制剂开发的主要挑战，用于征服耐药NSCLC。在该研究中，一系列新的9-杂环基取代的9h-嘌呤衍生物被设计为EGFR（L858 R / T790 M / C797S）酪氨酸激酶抑制剂。在这些化合物中，D4，D9，D11和D12显示出显着的抗增殖和EGFR（L858 R / T790 m / C797s）抑制活性。特别地，最有效的化合物D9分别显示出对HCC827和H1975细胞系的抗增殖，分别为0.00088和0.20μm。 D9禁止具有18nm的IC50值的EGFR（L858 R / T790 M / C797s）。此外，D9可以显着抑制EGFR磷酸化，诱导G0 / G1的凋亡，抑制细胞周期，并通过浓度依赖性方式抑制HCC827细胞系中的菌落形成。分子对接表明，在D9中引入环丙基磺酰胺基团导致突变体SER797的另外的两个氢键，这在产生有效的EGFR（L858R / T790M / C797S）抑制活性时起着关键作用。这些发现强烈表明，9-杂环基取代的9H-嘌呤衍生物是有前途的L858R / T790M / C797S突变体EGFR-TKI。与突变体SER797的额外氢键相互作用引入具有高效设计的有效方法，用于设计第四代EGFR-TKIS。 （c）2019年Elsevier Masson SAS。版权所有。

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