Medical Clinic and Policlinic II, Klinikum Rechts der Isar, TU Munich, 81675 Munich, Germany.
Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
Bioorg Chem. 2022 Feb;119:105505. doi: 10.1016/j.bioorg.2021.105505. Epub 2021 Nov 20.
Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.
靶向蛋白降解为失活癌症驱动因子提供了新的机会，并已成功进入临床。诱导选择性蛋白降解的方法包括蛋白酶体靶向嵌合体（PROTAC）技术和免疫调节（IMiDs）/下一代 Cereblon（CRBN）E3 连接酶调节药物（CELMoDs）。在这里，我们旨在基于 MYC-MAX 二聚化抑制剂 10058-F4 衍生物 28RH 和沙利度胺开发一种 MYC PROTAC，称为 MDEG-541。我们表明，胃肠道癌细胞系和原代患者来源类器官的亚组对 MDEG-541 敏感。尽管 MYC 表达受 CRBN、蛋白酶体和泛素依赖性调节，但我们提供的证据表明，MDEG-541 诱导了 CRBN 新底物的降解，包括 G1 到 S 期转变 1/2（GSPT1/2）和 Polo 样激酶 1（PLK1）。总之，我们已经建立了一种具有胃肠道癌活性的依赖于 CRBN 的相关癌症靶标降解剂。
