Journal article

Fragment screening for a protein-protein interaction inhibitor to WDR5

Matthew L Dennis, Benjamin J Morrow, Olan Dolezal, Anthony N Cuzzupe, Alexandra E Stupple, Janet Newman, John Bentley, Meghan Hattarki, Stewart D Nuttall, Richard C Foitzik, Ian P Street, Paul A Stupple, Brendon J Monahan, Thomas S Peat

Structural Dynamics | AIP Publishing | Published : 2019


The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the “WIN” site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is boun..

View full abstract


Funding Acknowledgements

We thank the Australian Synchrotron for beam time and the beamline scientists for their help. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron and made use of the ACRF detector. We also thank the C3 Crystallization Centre for all crystallization experiments. This project received funding from the Australian Government through the Cooperative Research Center for Cancer Therapeutics (from the Department of Industry, Innovation and Science (DIIS) Cooperative Research Centres Program). The CRC for Cancer Therapeutics partially funds its work through the sale of discoveries to pharmaceutical and biotech companies.