A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.

中文翻译：

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通过靶向ATP口袋中枢区域选择性抑制成纤维细胞生长因子受体4的方法

使用无偏筛选方法和已知激酶抑制剂支架的修饰，鉴定了多种选择性FGFR4抑制剂命中系列。在每种情况下，选择性的起源都与在位置552处FGFR4激酶结构域的中间铰链区域内保守性较差的半胱氨酸残基的相互作用相一致。靶向该区域可确定大小不同的非共价二氨基嘧啶系列， Cys552与2-氯吡啶进行SNAr反应的不可逆共价抑制剂，Cys552与2-甲酰基萘形成半硫缩醛加合物的可逆共价抑制剂系列。此外，