Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations
Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations
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DOI：
10.1021/acs.jmedchem.2c00168
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发表时间：
2022-05-12
影响因子：
7.3
通讯作者：
Ding, Ke
中科院分区：
文献类型：
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作者：
Chen, Hao;Lai, Mengzhen;Ding, Ke
针对非小细胞肺癌（NSCLC）患者表皮生长因子受体（EGFR）三级C797 S突变介导的耐药，目前临床上仍缺乏相应的研究，已经开发了几类腺苷5 '-三磷酸竞争性或变构性EGFRT 790 M/C797 S抑制剂和降解剂，但均未获得监管机构的批准。在此，我们报告了基于结构的设计，通过使用大环化策略，将构象受限的4-（1-乙基磺酰基-3-吲哚基）-2-苯基-氨基嘧啶作为新的EGFRT 790 M/C797 S抑制剂。代表性化合物18 J有效抑制EGFR 19 del/T790 M/C797和EGFRL 858 R/T790 M/C797 Smutants，IC 50值分别为15.8和23.6 nM，并抑制Ba/F3-EGFRL 858 R/T790 M/C797和Ba/F3-EGFR 19 del/T790 M/C797 S细胞，IC 50值分别为0.036和0.052 μ M，其效力是brigatinib的10-20倍。18 j也有效抑制EGFR 19 del/T790 M/C797 S突变的PC-9-OR NSCLC细胞增殖，IC 50值为0.644 μ M，但对亲本Ba/F3和A431细胞的效力较低。本研究为开发抗EGFRC 797 S介导的NSCLC耐药药物提供了一种新的先导化合物。
tertiary C797S mutation of epidermal growthfactor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need.Several classes of adenosine 5 '-triphosphate-competitive orallosteric EGFRT790M/C797Sinhibitors and degraders have beendeveloped, but none of them have received approval from theregulatory agencies. Herein, we report the structure-based design ofconformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenyl-aminopyrimidines as new EGFRT790M/C797Sinhibitors by using amacrocyclization strategy. Representative compound18jpotentlyinhibited EGFR19del/T790M/C797Sand EGFRL858R/T790M/C797Smutantswith IC50values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797Sand Ba/F3-EGFR19del/T790M/C797Scells withIC50values of 0.036 and 0.052 mu M, respectively, which is 10-20-fold more potent than brigatinib.18jalso potently inhibited theEGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50value of 0.644 mu M but was less potent for parentalBa/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance inNSCLC patients.