Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC.
Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC.
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DOI：
10.1016/j.ejmech.2023.116074
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发表时间：
2023-12
影响因子：
6.7
通讯作者：
Liping Hu;Shengmin Shi;Xiaomeng Song;Fangli Ma;Oulian Ji;Baohui Qi
中科院分区：
文献类型：
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作者：
Liping Hu;Shengmin Shi;Xiaomeng Song;Fangli Ma;Oulian Ji;Baohui Qi
我们从变构表皮生长因子受体抑制剂JBJ-04-125-02的结合方式和第三代表皮生长因子受体抑制剂的关键药效基团出发，设计合成了以(R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide(6q)为代表的一系列新型表皮生长因子受体抑制剂。对接研究表明，顶端化合物6q跨越了EGFR的正构和变构两个位置，形成了三个关键的氢键，残基Asp855、Lys745和Met793位于两个位置。生物活性评价表明，化合物6q对BA/F3-EGFRL858R/T790M/C797S和BA/F3-EGFRDel19/T790M/C797S细胞具有潜在的抑制活性，IC50值分别为0.42UμM和0.41UμM。此外，化合物6q对突变型非小细胞肺癌细胞株NCI-H1975-EGFRL858R/T790M/C797S表现出较好的抗肿瘤活性，其IC50值为0.82UμM，优于奥西美替尼(IC50值=2.94μM)、JBJ-04-12502(IC50值=33.66UμM)以及与奥西美替尼合用的IC50值(IC50值=1.25μM)。细胞周期停滞和细胞凋亡实验表明，化合物6q在0.8μM浓度下可促进NCI-H1975-EGFRL858R/T790M/C797S细胞的凋亡，未发现明显的细胞周期停滞。
Starting from the binding mode of allosteric EGFR inhibitor JBJ-04-125-02 and the key pharmacophore of the third-generation EGFR inhibitors, we designed and synthesized a novel series of EGFR inhibitors, represented by (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide (6q). Docking study demonstrated that top compound6qspanned orthosteric and allosteric sites of EGFR, and formed three key H-bonds with the residues Asp855, Lys745, and Met793 located in two sites. Biological evaluation indicated that compound6qshowed potential inhibitory activity against Ba/F3-EGFRL858R/T790M/C797Sand Ba/F3-EGFRDel19/T790M/C797Scells, with IC50values of 0.42 μM and 0.41 μM, respectively. Furthermore, compound6qshowed excellent activity against mutant NSCLC cell line NCI–H1975-EGFRL858R/T790M/C797Scells, with IC50value of 0.82 μM which was superior to that of osimertinib (IC50= 2.94 μM), JBJ-04-125-02 (IC50= 3.66 μM), and coadministration of JBJ-04-125-02 and osimertinib (IC50= 1.25 μM). Cell cycle arrest and cell apoptosis assay indicated that compound6qcould promote apoptosis of NCI–H1975-EGFRL858R/T790M/C797Scells at the concentration of 0.8 μM and no obvious cell cycle arrest was found.