2. Academic Validation
  3. Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core

Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core

  • J Med Chem. 2020 Jan 23;63(2):656-675. doi: 10.1021/acs.jmedchem.9b01608.
Jianhua Tian,  Kevin B Teuscher,  Erin R Aho,  Joseph R Alvarado,  Jonathan J Mills,  Kenneth M Meyers,  Rocco D Gogliotti,  Changho Han,  Jonathan D Macdonald,  Jiqing Sai,  J Grace Shaw,  John L Sensintaffar,  Bin Zhao,  Tyson A Rietz,  Lance R Thomas,  William G Payne,  William J Moore 1,  Gordon M Stott 1,  Jumpei Kondo 2 3,  Masahiro Inoue 2 3,  Robert J Coffey,  William P Tansey,  Shaun R Stauffer,  Taekyu Lee,  Stephen W Fesik
Affiliations

Affiliations

  • 1 Leidos Biomedical Research , Frederick National Laboratory for Cancer Research , Frederick , Maryland 21701 , United States.
  • 2 Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine , Kyoto University , Kyoto 606-8501 , Japan.
  • 3 Department of Biochemistry , Osaka International Cancer Institute , Osaka 541-8567 , Japan.
PMID: 31858797 DOI: 10.1021/acs.jmedchem.9b01608
Abstract

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site Binders inhibit proliferation in MYC-driven Cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.

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