2. Academic Validation
  3. Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

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

  • J Med Chem. 2021 Aug 12;64(15):10682-10710. 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
Affiliations

Affiliations

  • 1 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.
  • 2 Institut für Pharmazeutische Chemie, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 3 Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 4 Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
  • 5 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 6 Institut für Pharmazie und Lebensmittelchemie, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 7 Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 8 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • 9 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
  • 10 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • 11 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.
  • 12 Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 13 Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich, 85354 Freising, Germany.
PMID: 33980013 DOI: 10.1021/acs.jmedchem.1c00146
Abstract

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.

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