Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-13 , DOI: 10.1021/acs.jmedchem.1c00146
Anja Dölle _{1,

2} , Bikash Adhikari ₃ , Andreas Krämer _{1,

2} , Janik Weckesser _{1,

2} , Nicola Berner _{4,

5} , Lena-Marie Berger _{1,

2} , Mathias Diebold ₆ , Magdalena M Szewczyk ₇ , Dalia Barsyte-Lovejoy _{7,

8} , Cheryl H Arrowsmith _{7,

9,

10} , Jakob Gebel _{1,

11} , Frank Löhr _{1,

11} , Volker Dötsch _{1,

10} , Martin Eilers ₁₂ , Stephanie Heinzlmeir ₄ , Bernhard Kuster _{4,

5,

13} , Christoph Sotriffer ₆ , Elmar Wolf ₃ , Stefan Knapp _{1,

2,

5}

Affiliation

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.
Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Institut für Pharmazie und Lebensmittelchemie, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2M9, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University Frankfurt am Main, 60438 Frankfurt am Main, Germany.
Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich, 85354 Freising, Germany.

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.

中文翻译：

含有 WD 重复序列的蛋白质 5 (WDR5) 降解剂的设计、合成和评估

组蛋白 H3K4 甲基化是活跃转录基因的翻译后标志，由组蛋白甲基转移酶 (HMT) 及其调节支架蛋白引入。其中之一是含有 WD 重复序列的蛋白 5 (WDR5)，它也与控制长非编码 RNA 和包括 MYC 在内的转录因子有关。功能失调的 HMT 复合物的广泛影响和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 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。虽然此类化合物仅抑制 WDR5 相互作用的一个子集，但 WDR5 的化学诱导蛋白酶体降解可能代表一种针对所有致癌功能的优雅方式。本研究介绍了设计、合成、

更新日期：2021-05-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南