Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of -fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.

中文翻译：

---

发现 9H-嘧啶并[4,5-b]吲哚衍生物作为双重 RET/TRKA 抑制剂


异常的 RET 激酶信号在多种癌症中被激活，包括肺癌、甲状腺癌、乳腺癌、胰腺癌和前列腺癌。最近选择性 RET 抑制剂 pralsetinib 和 selpercatinib 的批准，已将 RET 激酶药物发现计划的重点转向选择性抑制剂的开发。然而，选择性抑制剂总是会失去功效，因为抑制剂的选择性性质给肿瘤带来了达尔文式的压力，使其通过选择新的致癌驱动因素来绕过治疗。此外，选择性抑制剂仅限于用于具有特定遗传背景的肿瘤，不涵盖不同的患者类别。在这里，我们报告了一种嘧啶吲哚 RET 抑制剂的鉴定，该抑制剂被发现也具有抗 TRK 活性。这种选择性双重 RET/TRK 抑制剂可用于具有 RET 和 TRK 遗传背景的肿瘤，并且还可以阻断从 RET 抑制剂治疗中选择的 β 融合。开发 RET/TRK 双重抑制剂的努力可以有益于涵盖更多样化的患者类别，同时还可以阻断新出现的耐药机制。