RT Journal Article
SR Electronic
T1 Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.12.439490
DO 10.1101/2021.04.12.439490
A1 Anja Dölle
A1 Bikash Adhikari
A1 Andreas Krämer
A1 Janik Weckesser
A1 Nicola Berner
A1 Lena-Marie Berger
A1 Mathias Diebold
A1 Magdalena M. Szewczyk
A1 Dalia Barsyte-Lovejoy
A1 Cheryl H. Arrowsmith
A1 Jakob Gebel
A1 Frank Löhr
A1 Volker Dötsch
A1 Martin Eilers
A1 Stephanie Heinzlmeir
A1 Bernhard Küster
A1 Christoph Sotriffer
A1 Elmar Wolf
A1 Stefan Knapp
YR 2021
UL http://biorxiv.org/content/early/2021/04/12/2021.04.12.439490.abstract
AB Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (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 non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs 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 function. 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.Competing Interest StatementThe authors have declared no competing interest.ASH2Labsent, small or homeotic-2 likeBRETbioluminescence Resonance Energy TransferDSFdifferential scanning fluorimetryHMTHistone methyltransferaseITCisothermal titration calorimetryKMTLysine methyltransferaseMbIIIbMyc box IIIbMLLmixed lineage leukemiaPROTACProteolysis targeting chimeraRBBP5retinoblastoma binding protein 5SETSu(var)3-9, Enhancer-of-zeste and TrithoraxWBMWDR5-bindingWDR5WD-repreat containing protein 5WINWDR5-interacting