posted on 2021-05-13, 08:43authored byAnja Dölle, Bikash Adhikari, Andreas Krämer, Janik Weckesser, Nicola Berner, Lena-Marie Berger, Mathias Diebold, Magdalena M. Szewczyk, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Jakob Gebel, Frank Löhr, Volker Dötsch, Martin Eilers, Stephanie Heinzlmeir, Bernhard Kuster, Christoph Sotriffer, Elmar Wolf, Stefan Knapp
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.