Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences (BMLS), Goethe University Frankfurt am Main, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
Institut für Pharmazeutische Chemie, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
J Med Chem. 2021 Aug 12;64(15):10682-10710. doi: 10.1021/acs.jmedchem.1c00146. Epub 2021 May 13.
Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.
组蛋白 H3K4 甲基化是转录活跃基因的翻译后标志,由组蛋白甲基转移酶(HMT)及其调节支架蛋白引入。其中之一是 WD 重复蛋白 5(WDR5),它也与控制长非编码 RNA 和转录因子(包括 MYC)有关。功能失调的 HMT 复合物的广泛影响以及不同肿瘤类型中通常上调的 MYC 水平表明 WDR5 是一个有吸引力的药物靶点。事实上,已经开发了针对 WDR5 上两个蛋白质相互作用界面的蛋白质-蛋白质界面抑制剂。虽然这些化合物仅抑制 WDR5 相互作用的一部分,但化学诱导的 WDR5 蛋白酶体降解可能是靶向所有致癌功能的一种巧妙方法。本研究提出了基于两个 WIN 结合支架的两种不同的 WDR5 降解剂系列的设计、合成和评价,并表明连接子的性质和长度强烈影响降解效果。