Department of Chemistry and Chemical Biology, Technical University of Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
J Med Chem. 2013 Jul 25;56(14):5757-72. doi: 10.1021/jm4004076. Epub 2013 Jul 10.
Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.
在位于“守门员”位置的催化结构域中的突变代表了激酶最突出的耐药变体，极大地削弱了针对癌症的靶向治疗的效果。了解耐药性在分子和原子水平上的机制，将有助于设计和开发具有克服这些耐药性突变潜力的抑制剂。在此，通过在抑制剂核心结构中引入适应性元件，我们基于结构开发了 II 型混合抑制剂，以克服 cSrc-T338M 中的“守门员”耐药突变，以及临床相关的酪氨酸激酶 KIT-T670I 和 Abl-T315I 变体，这些是胃肠道间质瘤（GIST）和慢性髓性白血病（CML）中的重要靶点。通过蛋白质 X 射线晶体学，我们确认了在 cSrc 中预期的结合模式，这对于克服各自的耐药性至关重要。更重要的是，新型化合物在生化和细胞研究中有效地抑制了临床相关的 KIT 和 Abl 的“守门员”突变体。
