Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, 53705, USA.
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
Chembiochem. 2023 Oct 17;24(20):e202300482. doi: 10.1002/cbic.202300482. Epub 2023 Aug 22.
Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.
蛋白水解靶向嵌合体（PROTACs）是一种很有前途的治疗策略，可利用泛素-蛋白酶体系统选择性地促进蛋白质靶标的降解。在 PROTAC 技术发现的有限数量的 E3 连接酶配体中，cereblon（CRBN）E3 连接酶的配体，如泊马度胺、沙利度胺或来那度胺，是最常用于开发 PROTACs 的配体。我们小组之前曾报道过，在 lenalidomide 的 C4 位上可以容忍苯环作为 CRBN 的配体来开发 PROTACs。在此，我们报告了一种模块化化学平台，可通过 Suzuki 交叉偶联反应将各种邻位、间位和对位取代的苯基高效地连接到 lenalidomide 的 C4 位上，从而可以系统地研究连接子效应对开发针对任何靶标的 PROTACs 的影响。我们通过制备具有不同连接子的十二个 lenalidomide 衍生的 CRBN E3 连接酶配体来检查底物范围。
