Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion–positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion–positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion–positive cancer.

中文翻译：

---

选择性TRK抑制剂CH7057288对抗TRK融合驱动的癌症

由于发生在多种癌症类型中的基因融合，原肌球蛋白受体激酶 (TRK) 家族的成员以其组成型激活形式表达。我们已将 CH7057288 鉴定为一种有效且选择性的 TRK 抑制剂，属于一种新型化学类别。CH7057288 在无细胞激酶测定中显示出对 TRKA、TRKB 和 TRKC 的选择性抑制活性，并抑制 TRK 融合阳性细胞系的增殖，但不抑制 TRK 阴性细胞系的增殖。在皮下植入的 TRK 融合阳性细胞的异种移植肿瘤模型中观察到强烈的体内肿瘤生长抑制。此外，在模拟脑转移的颅内植入模型中，CH7057288 显着诱导肿瘤消退并提高无事件生存率。最近，据报道，在接受临床开发的 TRK 抑制剂治疗后出现疾病进展的患者中，TRK 激酶结构域中的耐药突变。我们的化合物对这些抗性突变体之一保持了与野生型 TRK 相似的体外和体内活性水平。TRKA 和 CH7057288 复合物的 X 射线晶体结构支持对突变体的活性。此外，基因表达分析显示，CH7057288 抑制了作为 TRK 融合下游信号传导的 MAPK 和 E2F 通路。因此，CH7057288 可能是一种有前途的 TRK 融合阳性癌症治疗剂。我们的化合物对这些抗性突变体之一保持了与野生型 TRK 相似的体外和体内活性水平。TRKA 和 CH7057288 复合物的 X 射线晶体结构支持对突变体的活性。此外，基因表达分析显示，CH7057288 抑制了作为 TRK 融合下游信号传导的 MAPK 和 E2F 通路。因此，CH7057288 可能是一种有前途的 TRK 融合阳性癌症治疗剂。我们的化合物对这些抗性突变体之一保持了与野生型 TRK 相似的体外和体内活性水平。TRKA 和 CH7057288 复合物的 X 射线晶体结构支持对突变体的活性。此外，基因表达分析显示，CH7057288 抑制了作为 TRK 融合下游信号传导的 MAPK 和 E2F 通路。因此，CH7057288 可能是一种有前途的 TRK 融合阳性癌症治疗剂。