Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany.
Department of Medical Oncology, Sarcoma Centre West German Cancer Centre University Duisburg-Essen, Medical School , Hufelandstraße 55, D-45122 Essen, Germany.
J Med Chem. 2017 Nov 9;60(21):8801-8815. doi: 10.1021/acs.jmedchem.7b00841. Epub 2017 Oct 24.
In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.
在现代癌症治疗中，使用针对受体酪氨酸激酶（RTKs）的小分子有机化合物已被证明是一种有价值的策略。癌细胞与 RTKs 相关的失调信号通路的关联是靶向癌症治疗的关键要素。酪氨酸激酶 mast/stem cell 生长因子受体 KIT 就是一个与临床相关的 RTK 的例子。KIT 是胃肠道间质瘤（GIST）和慢性髓性白血病（CML）的癌症治疗靶点。然而，催化结构域内获得的耐药性突变会降低这种策略的疗效，也是治疗失败的最常见原因。在这里，我们提出了基于结构的设计和合成新型 II 型激酶抑制剂，以克服 KIT 中的这些突变。生化和细胞研究揭示了具有抑制突变 KIT 潜力的分子。
