The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC₅₀: 46 nM) and c-KIT kinase (IC₅₀: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 μM among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery.

中文翻译：

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发现4-甲基-N-（4-（（4-甲基哌嗪-1-基）甲基）-3-（三氟甲基）苯基）-3-（（1-烟酰哌啶-4-基）氧基）苯甲酰胺（CHMFL- ABL / KIT-155）作为新型高强度II型ABL / KIT双激酶抑制剂，具有明显的铰链结合

发现了一种新型的有效II型ABL / c-KIT双激酶抑制剂化合物34（CHMFL-ABL / KIT-155），该化合物利用了NH在激酶主链上形成的氢键和34的羰基氧作为独特的铰链结合进行说明。34有效地抑制了纯化ABL（IC ₅₀：46纳米）和c-KIT激酶（IC ₅₀：75纳米）在生物化学测定和在1μM的468种激酶中的浓度显示高选择性（S分数（1）= 0.03） KINOMEscan分析中的/突变体。它通过阻断BCR-ABL / c-KIT介导的信号通路，阻止细胞周期进程和诱导凋亡，对BCR-ABL / c-KIT驱动的CML / GISTs癌细胞系表现出强大的抗增殖活性。34具有良好的口服PK特性，并有效抑制K562（CML）和GIST-T1（GISTs）细胞介导的异种移植小鼠模型中的肿瘤进展。34的独特铰链结合模式为扩大II型激酶抑制剂发现的化学结构多样性提供了一种新的药效基团。