Rational design and synthesis of 2,4-dichloro-6-methyl pyrimidine derivatives as potential selective EGFRT790M/L858R inhibitors for the treatment of non-small cell lung cancer,Archiv der Pharmazie

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Rational design and synthesis of 2,4-dichloro-6-methyl pyrimidine derivatives as potential selective EGFRT790M/L858R inhibitors for the treatment of non-small cell lung cancer
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2024-02-21 , DOI: 10.1002/ardp.202300736
Lei Duan ₁ , Cilong Chu ₁ , Xiaoling Huang ₁ , Huizhi Yao ₁ , Jie Wen ₁ , Rui Chen ₁ , Caolin Wang ₂ , Yuanbiao Tu ₃ , Qiaoli Lv ₄ , Qingshan Pan ₁ , Shan Xu ₁

Affiliation

Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today. Based on the previous studies on AZD-9291, we designed and synthesized two series of 2,4-dichloro-6-methylpyrimidine derivatives, 19 compounds in total, as potential inhibitors of the EGFR kinase. The most promising compound, L-18, showed better inhibitory activity (81.9%) and selectivity against EGFR^T790M/L858R kinase. In addition, L-18 showed strong antiproliferative activity against H1975 cells with an IC₅₀ value of 0.65 ± 0.06 μM and no toxicity to normal cells (LO-2). L-18 was able to dose-dependently induce the apoptosis of H1975 cells and produced a cell-cycle-blocking effect, and it can also dose-dependently inhibit the migration and invasion of H1975 cells. L-18 also showed in vivo anticancer efficacy in H1975 cells xenograft mice. We also performed a series of in vivo and in vitro toxicological evaluations of compound L-18, which did not cause obvious injury in mice during administration. These results suggest that L-18 may be a promising drug candidate that warrants further investigation.

中文翻译：

合理设计和合成2,4-二氯-6-甲基嘧啶衍生物作为治疗非小细胞肺癌的潜在选择性EGFRT790M/L858R抑制剂

许多非小细胞肺癌（NSCLC）患者最初受益于表皮生长因子受体（EGFR）靶向治疗。不幸的是，最终会产生不同程度的耐药性或副作用。克服和预防EGFR抑制剂的耐药性和副作用已成为当今研究的热点话题。在前期AZD-9291研究的基础上，我们设计合成了两个系列的2,4-二氯-6-甲基嘧啶衍生物，共19个化合物，作为EGFR激酶的潜在抑制剂。最有前途的化合物L-18对 EGFR ^T790M/L858R激酶表现出更好的抑制活性 (81.9%) 和选择性。此外， L-18对 H1975 细胞表现出很强的抗增殖活性，IC ₅₀值为 0.65 ± 0.06 μM，对正常细胞没有毒性 (LO-2)。 L-18能够剂量依赖性地诱导H1975细胞凋亡并产生细胞周期阻断作用，并且还能够剂量依赖性地抑制H1975细胞的迁移和侵袭。 L-18还在H1975细胞异种移植小鼠中显示出体内抗癌功效。我们还对化合物L-18进行了一系列体内外毒理学评价，给药过程中并未对小鼠造成明显的损伤。这些结果表明L-18可能是一种有前途的候选药物，值得进一步研究。

更新日期：2024-02-21

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