PDF(Pubmed)
Abstract：
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 NTRK-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.
摘要：
异常的RET激酶信号在许多癌症中被激活，包括肺癌，甲状腺，乳房,胰腺,还有前列腺.最近批准的选择性RET抑制剂，普雷替尼和selpercatinib，已将RET激酶药物发现计划的重点转移到选择性抑制剂的开发上。然而,选择性抑制剂总是失去效力,因为抑制剂的选择性性质通过选择新的致癌驱动因素对肿瘤施加类似达尔文的压力以绕过治疗。Further,选择性抑制剂被限制用于具有特定遗传背景的肿瘤,这些肿瘤不包括不同的患者类别.在这里，我们报告了发现还具有针对TRK活性的嘧啶吲哚RET抑制剂的鉴定。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,并且还可提供对选自RET抑制剂治疗的NTRK融合体的阻断。开发双重RET/TRK抑制剂的努力在涵盖更多样化的患者类别方面可能是有益的,同时还实现针对出现的抗性机制的阻断。
