Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core
- Vanderbilt Univ., Nashville, TN (United States)
- Frederick National Lab. for Cancer Research, MD (United States)
- Kyoto Univ. (Japan); Osaka International Cancer Inst. (Japan)
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. In this paper, 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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- National Institutes of Health (NIH); National Cancer Institute (NCI); USDOE Office of Science (SC); Michigan Economic Development Corporation and Michigan Technology Tri-Corridor
- Grant/Contract Number:
- 1S-10RR025677-01; AC02-06CH11357; 085P1000817; CA211305
- OSTI ID:
- 1598029
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 63, Issue 2; ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
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