Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders
| Autor: | Andreas Krämer, Elmar Wolf, Frank Löhr, Dalia Barsyte-Lovejoy, Martin Eilers, Mathias Diebold, Magdalena M. Szewczyk, Christoph A. Sotriffer, Cheryl H. Arrowsmith, Lena-Marie Berger, Stephanie Heinzlmeir, Jakob Gebel, Bernhard Kuster, Volker Dötsch, Stefan Knapp, Bikash Adhikari, Anja Dölle, Janik Weckesser, Nicola Berner |
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| Jazyk: | angličtina |
| Předmět: |
Male
Scaffold protein Dihydropyridines Antineoplastic Agents Ligands 01 natural sciences Structure-Activity Relationship 03 medical and health sciences Drug Discovery Humans WDR5 Gene Transcription factor Cells Cultured 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology Chemistry WD Repeat-Containing Protein 5 Biphenyl Compounds Intracellular Signaling Peptides and Proteins 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry Histone Drug Design Histone methyltransferase biology.protein Molecular Medicine Female Linker |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00146 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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