Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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

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. 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.

Authors:
 [1];  [1];  [1];  [1]; ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [3] more »;  [1];  [1];  [1];  [1]; ORCiD logo [1] « less
+ Show Author Affiliations
  1. Vanderbilt Univ., Nashville, TN (United States)
  2. Frederick National Lab. for Cancer Research, MD (United States)
  3. Kyoto Univ. (Japan); Osaka International Cancer Inst. (Japan)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Cancer Institute (NCI); USDOE Office of Science (SC); Michigan Economic Development Corporation and Michigan Technology Tri-Corridor
OSTI Identifier:
1598029
Grant/Contract Number:  
1S-10RR025677-01; AC02-06CH11357; 085P1000817; CA211305
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 63; Journal Issue: 2; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Cells; Inhibitors; Cancer; Peptides and proteins; Genetics

Citation Formats

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, and Fesik, Stephen W. Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core. United States: N. p., 2019. Web. doi:10.1021/acs.jmedchem.9b01608.
Copy to clipboard
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. Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core. United States. https://doi.org/10.1021/acs.jmedchem.9b01608
Copy to clipboard
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, and Fesik, Stephen W. Fri . "Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core". United States. https://doi.org/10.1021/acs.jmedchem.9b01608. https://www.osti.gov/servlets/purl/1598029.
Copy to clipboard
@article{osti_1598029,
title = {Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core},
author = {Tian, Jianhua and Teuscher, Kevin B. and Aho, Erin R. and Alvarado, Joseph R. and Mills, Jonathan J. and Meyers, Kenneth M. and Gogliotti, Rocco D. and Han, Changho and Macdonald, Jonathan D. and Sai, Jiqing and Shaw, J. Grace and Sensintaffar, John L. and Zhao, Bin and Rietz, Tyson A. and Thomas, Lance R. and Payne, William G. and Moore, William J. and Stott, Gordon M. and Kondo, Jumpei and Inoue, Masahiro and Coffey, Robert J. and Tansey, William P. and Stauffer, Shaun R. and Lee, Taekyu and Fesik, Stephen W.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.9b01608},
journal = {Journal of Medicinal Chemistry},
number = 2,
volume = 63,
place = {United States},
year = {Fri Dec 20 00:00:00 EST 2019},
month = {Fri Dec 20 00:00:00 EST 2019}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acs.jmedchem.9b01608
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 17 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

WD40 proteins propel cellular networks
journal, October 2010

  • Stirnimann, Christian U.; Petsalaki, Evangelia; Russell, Robert B.
  • Trends in Biochemical Sciences, Vol. 35, Issue 10
  • DOI: 10.1016/j.tibs.2010.04.003

Structure and function of WD40 domain proteins
journal, March 2011

Moonlighting with WDR5: A Cellular Multitasker
journal, January 2018

  • Guarnaccia, Alissa; Tansey, William
  • Journal of Clinical Medicine, Vol. 7, Issue 2
  • DOI: 10.3390/jcm7020021

WDR5 Expression Is Prognostic of Breast Cancer Outcome
journal, September 2015

Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
journal, September 2015

  • Zhu, Jiajun; Sammons, Morgan A.; Donahue, Greg
  • Nature, Vol. 525, Issue 7568
  • DOI: 10.1038/nature15251

Discovery of Potent 2-Aryl-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design
journal, June 2018

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
journal, March 2019

A Conserved Arginine-containing Motif Crucial for the Assembly and Enzymatic Activity of the Mixed Lineage Leukemia Protein-1 Core Complex
journal, October 2008

  • Patel, Anamika; Vought, Valarie E.; Dharmarajan, Venkatasubramanian
  • Journal of Biological Chemistry, Vol. 283, Issue 47
  • DOI: 10.1074/jbc.m806317200

MLL: a histone methyltransferase disrupted in leukemia
journal, October 2004

Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes
journal, August 2016

  • Alicea-Velázquez, Nilda L.; Shinsky, Stephen A.; Loh, Daniel M.
  • Journal of Biological Chemistry, Vol. 291, Issue 43
  • DOI: 10.1074/jbc.m116.752626

Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC
journal, May 2015

Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation
journal, February 2015

  • Chen, Xu; Xie, Weibin; Gu, Peng
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep08293

PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407
journal, March 2017

Up‐regulated WDR5 promotes gastric cancer formation by induced cyclin D1 expression
journal, December 2017

  • Sun, Wei; Guo, Fuchao; Liu, Mingkai
  • Journal of Cellular Biochemistry, Vol. 119, Issue 4
  • DOI: 10.1002/jcb.26491

A Twist1-MLL-WDR5-HOTTIP Complex Regulates HOXA9 Chromatin to Facilitate Metastasis of Prostate Cancer
journal, September 2014

  • Tran, P. T.; Gajula, R.; Williams, R.
  • International Journal of Radiation Oncology*Biology*Physics, Vol. 90, Issue 1
  • DOI: 10.1016/j.ijrobp.2014.05.691

Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma
journal, April 2018

  • Wu, Yaping; Diao, Pengfei; Li, Zhongwu
  • Journal of Oral Pathology & Medicine, Vol. 47, Issue 5
  • DOI: 10.1111/jop.12708

WDR5 high expression and its effect on tumorigenesis in leukemia
journal, May 2016

The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer
journal, November 2018

The MLL recombinome of acute leukemias in 2013
journal, April 2013

The Pathogenesis of Mixed-Lineage Leukemia
journal, February 2012

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches
journal, February 2017

MLL translocations, histone modifications and leukaemia stem-cell development
journal, November 2007

  • Krivtsov, Andrei V.; Armstrong, Scott A.
  • Nature Reviews Cancer, Vol. 7, Issue 11
  • DOI: 10.1038/nrc2253

Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia
journal, January 2014

MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia
journal, June 2017

Targeting WDR5: A WINning Anti-Cancer Strategy?
journal, January 2019

Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
journal, July 2015

  • Grebien, Florian; Vedadi, Masoud; Getlik, Matthäus
  • Nature Chemical Biology, Vol. 11, Issue 8
  • DOI: 10.1038/nchembio.1859

Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)
journal, March 2016

  • Getlik, Matthäus; Smil, David; Zepeda-Velázquez, Carlos
  • Journal of Medicinal Chemistry, Vol. 59, Issue 6
  • DOI: 10.1021/acs.jmedchem.5b01630

Analysis of the Binding of Mixed Lineage Leukemia 1 (MLL1) and Histone 3 Peptides to WD Repeat Domain 5 (WDR5) for the Design of Inhibitors of the MLL1−WDR5 Interaction
journal, July 2010

  • Karatas, Hacer; Townsend, Elizabeth C.; Bernard, Denzil
  • Journal of Medicinal Chemistry, Vol. 53, Issue 14
  • DOI: 10.1021/jm100139b

Retaining cell-cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer
journal, March 2011

  • Kondo, J.; Endo, H.; Okuyama, H.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 15
  • DOI: 10.1073/pnas.1015938108

High-throughput screening in colorectal cancer tissue-originated spheroids
journal, November 2018

  • Kondo, Jumpei; Ekawa, Tomoya; Endo, Hiroko
  • Cancer Science, Vol. 110, Issue 1
  • DOI: 10.1111/cas.13843

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)
journal, April 2015

The Myc oncoprotein as a therapeutic target for human cancer
journal, August 2006

MYC as a regulator of ribosome biogenesis and protein synthesis
journal, April 2010

  • van Riggelen, Jan; Yetil, Alper; Felsher, Dean W.
  • Nature Reviews Cancer, Vol. 10, Issue 4
  • DOI: 10.1038/nrc2819

Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization
journal, September 2004

  • Nikolovska-Coleska, Zaneta; Wang, Renxiao; Fang, Xueliang
  • Analytical Biochemistry, Vol. 332, Issue 2
  • DOI: 10.1016/j.ab.2004.05.055

Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases
journal, May 2015

  • Ferry, Joseph J.; Smith, Robert F.; Denney, Natalie
  • ASSAY and Drug Development Technologies, Vol. 13, Issue 4
  • DOI: 10.1089/adt.2015.646
    Sort by:
    [ × clear filter / sort ]

    Similar Records in DOE PAGES and OSTI.GOV collections: