构象受限的 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine 衍生物作为靶向 T790M/C797S 突变的新第四代表皮生长因子受体抑制剂,Journal of Medicinal Chemistry

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构象受限的 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine 衍生物作为靶向 T790M/C797S 突变的新第四代表皮生长因子受体抑制剂
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-04-21 , DOI: 10.1021/acs.jmedchem.2c00168
Hao Chen ₁ , Mengzhen Lai _{2,

3} , Tao Zhang ₂ , Yuqing Chen ₁ , Linjiang Tong ₂ , Sujie Zhu ₄ , Yang Zhou ₁ , Xiaomei Ren ₅ , Jian Ding _{2,

6} , Hua Xie _{2,

6,

7} , Xiaoyun Lu ₁ , Ke Ding _{1,

5}

Affiliation

非小细胞肺癌 (NSCLC) 患者中表皮生长因子受体 (EGFR) 介导的耐药性的三级 C797S 突变仍是未满足的临床需求。已开发出几类 5'-三磷酸腺苷竞争性或变构 EGFR ^T790M/C797S抑制剂和降解剂，但均未获得监管机构的批准。在此，我们通过使用大环化策略报告了构象受限的 4-(1-ethylsufonyl-3-indolyl)-2-苯基氨基嘧啶作为新型 EGFR ^T790M/C797S抑制剂的基于结构的设计。代表性化合物18j有效抑制 EGFR ^{19del/T790M/C797S}和 EGFR ^{L858R/T790M/C797S}突变体，IC ₅₀值分别为 15.8 和 23.6 nM，抑制 Ba/F3-EGFR ^{L858R/T790M/C797S}和 Ba/F3-EGFR ^{19del/T790M/C797S}细胞，IC ₅₀值分别为 0.036 和 0.052 μM，高出 10-20 倍比布加替尼强。18j还有效抑制 EGFR ^{19del/T790M/C797S}突变的 PC-9-OR NSCLC 细胞增殖，IC ₅₀值为 0.644 μM，但对亲本 Ba/F3 和 A431 细胞的效力较低。该研究为药物发现提供了一种新的先导化合物，以对抗NSCLC 患者中EGFR ^{C797S介导的耐药性。}

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Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations

Tertiary C797S mutation of epidermal growth factor 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 or allosteric EGFR^T790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR^T790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR^{19del/T790M/C797S} and EGFR^{L858R/T790M/C797S} mutants with IC₅₀ values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR^{L858R/T790M/C797S} and Ba/F3-EGFR^{19del/T790M/C797S} cells with IC₅₀ values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR^{19del/T790M/C797S}-mutated PC-9-OR NSCLC cell proliferation with an IC₅₀ value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR^C797S-mediated resistance in NSCLC patients.

更新日期：2022-04-21

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