While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

中文翻译：

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的发现ñ - （4 - {[5-氟-7-（2-甲氧基乙氧基）喹唑啉-4-基]氨基}苯基）-2- [4-（丙-2-基）-1- ħ -1,2- ，3-triazol-1-yl] acetamide（AZD3229），一种有效的Pan-KIT突变抑制剂，用于治疗胃肠道间质瘤

尽管通过应用能够抑制KIT驱动的增殖的靶向酪氨酸激酶抑制剂，胃肠道间质瘤（GIST）的治疗发生了革命性变化，但该激酶的多种突变却驱动了对既定疗法的耐药性。在这里，我们描述了有效的pan-KIT突变激酶抑制剂的鉴定，该抑制剂可以在不受多靶点药物所见的耐受性问题限制的情况下给药。这项工作致力于通过使用基于结构的设计来鉴定和优化现有激酶支架。从一系列先前报道的酪氨酸激酶PDGFRα的基于苯氧基喹唑啉和喹啉的抑制剂开始，优化了针对多种突变KIT驱动的Ba / F3细胞系的效能，特别着重于降低针对KDR驱动的细胞模型的活性，以限制二线和三线GIST治疗中常见的高血压可能性。AZD3229展示了在宽细胞面板上有效的一位数nM生长抑制作用，对KDR驱动的作用有良好的余地。可以通过水分子与活性位点中的蛋白质和配体的相互作用来合理地选择对KDR的选择性，并且它的动蛋白选择性类似于已获批准的GIST试剂中最好的。该化合物具有极好的跨物种药代动力学，对靶标具有强大的药效抑制作用，并且在几种GIST体内模型中均具有活性。AZD3229展示了在宽细胞面板上有效的一位数nM生长抑制作用，对KDR驱动的作用有良好的余地。可以通过水分子与活性位点中的蛋白质和配体之间的相互作用来合理地选择对KDR的选择性，并且它的动蛋白选择性类似于已获批准的GIST最佳药剂。该化合物具有极好的跨物种药代动力学，对靶标具有强大的药效抑制作用，并且在几种GIST体内模型中均具有活性。AZD3229展示了在宽细胞面板上有效的一位数nM生长抑制作用，对KDR驱动的作用有良好的余地。可以通过水分子与活性位点中的蛋白质和配体之间的相互作用来合理地选择对KDR的选择性，并且它的动蛋白选择性类似于已获批准的GIST最佳药剂。该化合物具有极好的跨物种药代动力学，对靶标具有强大的药效抑制作用，并且在几种GIST体内模型中均具有活性。