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

Tian, Jianhua; Teuscher, Kevin B.; Aho, Erin R.; Alvarado, Joseph R.; Mills, Jonathan J.; Meyers, Kenneth M.; Gogliotti, Rocco D.; Han, Changho; Macdonald, Jonathan D.; Sai, Jiqing; Shaw, J. Grace; Sensintaffar, John L.; Zhao, Bin; Rietz, Tyson A.; Thomas, Lance R.; Payne, William G.; Moore, William J.; Stott, Gordon M.; Kondo, Jumpei; Inoue, Masahiro; Coffey, Robert J.; Tansey, William P.; Stauffer, Shaun R.; Lee, Taekyu; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.9b01608

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

Journal Article · Thu Dec 19 23:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.9b01608· OSTI ID:1598029

Tian, Jianhua ^[1]; Teuscher, Kevin B. ^[1]; Aho, Erin R. ^[1]; Alvarado, Joseph R. ^[1]; ^[1]; Meyers, Kenneth M. ^[1]; Gogliotti, Rocco D. ^[1]; Han, Changho ^[1]; Macdonald, Jonathan D. ^[1]; Sai, Jiqing ^[1]; Shaw, J. Grace ^[1]; Sensintaffar, John L. ^[1]; Zhao, Bin ^[1]; Rietz, Tyson A. ^[1]; Thomas, Lance R. ^[1]; Payne, William G. ^[1]; Moore, William J. ^[2]; Stott, Gordon M. ^[2]; Kondo, Jumpei ^[3]; Inoue, Masahiro ^[3] more »

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.

View Accepted Manuscript (DOE)

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:: AC02-06CH11357

OSTI ID:: 1598029

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 2 Vol. 63; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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