Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Conrad Prebys Centre for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
Bioorg Med Chem. 2024 May 15;106:117749. doi: 10.1016/j.bmc.2024.117749. Epub 2024 May 9.
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.
异常 RET 激酶信号在许多癌症中被激活，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 抑制剂普拉替尼和塞尔帕替尼的获批，将 RET 激酶药物研发项目的重点转向了选择性抑制剂的开发。然而，选择性抑制剂的疗效不可避免地会下降，因为抑制剂的选择性会对肿瘤产生达尔文式的压力，使其通过选择新的致癌驱动因素来逃避治疗。此外，选择性抑制剂仅限于具有特定遗传背景的肿瘤使用，这些肿瘤不能涵盖不同的患者群体。在这里，我们报告了一种嘧啶并吲哚 RET 抑制剂的鉴定，该抑制剂也对 TRK 具有活性。这种选择性的双重 RET/TRK 抑制剂可用于具有 RET 和 TRK 遗传背景的肿瘤，并可阻断从 RET 抑制剂治疗中选择的 NTRK 融合。开发双重 RET/TRK 抑制剂的努力在涵盖更多不同患者群体的同时，也可以针对新兴的耐药机制进行阻断，这是有益的。
