Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode,Journal of Medicinal Chemistry

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Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-22 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01907
Aoli Wang _{1,

2} , Xixiang Li _{1,

3} , Hong Wu _{1,

3} , Fengming Zou _{1,

3} , Xiao-E Yan ₄ , Cheng Chen _{1,

2} , Chen Hu _{1,

2} , Kailin Yu _{1,

2} , Wenchao Wang _{1,

3} , Peng Zhao ₄ , Jiaxin Wu _{1,

2} , Ziping Qi _{1,

3} , Wei Wang _{1,

3} , Beilei Wang _{1,

2} , Li Wang _{1,

2} , Tao Ren ₅ , Shanchun Zhang _{3,

6} , Cai-Hong Yun ₄ , Jing Liu _{1,

3} , Qingsong Liu _{1,

2,

3,

5}

Affiliation

On the basis of Ibrutinib’s core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct “DFG-in-C-helix-out” inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

中文翻译：

（R）-1-（3-（4-氨基-3-（3-氯-4-（吡啶-2-基甲氧基）苯基）-1）H-吡唑并[3,4- d ]嘧啶-1-的发现yl）piperidin-1-yl）prop-2-en-1-one（CHMFL-EGFR-202）作为具有独特结合模式的新型不可逆EGFR突变激酶抑制剂

基于对EGFR T790M突变体具有中等活性的依鲁替尼的核心药效基团，我们发现了新型表皮生长因子受体（EGFR）抑制剂化合物19（CHMFL-EGFR-202），该化合物可有效抑制EGFR初级突变体（L858R，del19）和耐药突变体L858R / T790M。在KINOMEscan分析中测试的468种激酶/突变体中，化合物19表现出良好的选择性（S评分（1）= 0.02）。特别地，它没有表现出针对INSR和IGF1R激酶的明显活性。X射线晶体结构表明，这类抑制剂与Cys797形成了独特的“ DFG-in-C-helix-out”非活性EGFR构象共价键。化合物19对EGFR突变驱动的非小细胞肺癌（NSCLC）细胞系（例如H1975，PC9，HCC827和H3255）具有较强的抗增殖作用，但对野生型EGFR表达细胞却没有抑制作用。在H1975和PC9细胞接种的异种移植小鼠模型中，化合物19表现出剂量依赖性的肿瘤生长抑制功效，而没有明显的毒性。化合物19可能是EGFR突变驱动的NSCLC的潜在候选药物。

更新日期：2017-03-22

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