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Title: 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

Abstract

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. In this a paper, we describe the discovery of potent and selective WDR5-WINsite inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5$$H$$pyrrolo[1,2-$$a$$]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.

Authors:
 [1];  [1];  [1]; ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [1]
  1. Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC); Michigan Economic Development Corporation and Michigan Technology Tri-Corridor; National Cancer Institute (NCI)
OSTI Identifier:
1499757
Grant/Contract Number:  
1S-10RR025677-01; AC02-06CH11357; 085P1000817; HHSN261200800001E; CA200709; CA68485
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 13; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; X-rays; Amides; Peptides and proteins; Chemical structure; Inhibitors

Citation Formats

Wang, Feng, Jeon, Kyu Ok, Salovich, James M., Macdonald, Jonathan D., Alvarado, Joseph, Gogliotti, Rocco D., Phan, Jason, Olejniczak, Edward T., Sun, Qi, Wang, Shidong, Camper, DeMarco, Yuh, Joannes P., Shaw, J. Grace, Sai, Jiqing, Rossanese, Olivia W., Tansey, William P., Stauffer, Shaun R., and Fesik, Stephen W. 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. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b00375.
Wang, Feng, Jeon, Kyu Ok, Salovich, James M., Macdonald, Jonathan D., Alvarado, Joseph, Gogliotti, Rocco D., Phan, Jason, Olejniczak, Edward T., Sun, Qi, Wang, Shidong, Camper, DeMarco, Yuh, Joannes P., Shaw, J. Grace, Sai, Jiqing, Rossanese, Olivia W., Tansey, William P., Stauffer, Shaun R., & Fesik, Stephen W. 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. United States. https://doi.org/10.1021/acs.jmedchem.8b00375
Wang, Feng, Jeon, Kyu Ok, Salovich, James M., Macdonald, Jonathan D., Alvarado, Joseph, Gogliotti, Rocco D., Phan, Jason, Olejniczak, Edward T., Sun, Qi, Wang, Shidong, Camper, DeMarco, Yuh, Joannes P., Shaw, J. Grace, Sai, Jiqing, Rossanese, Olivia W., Tansey, William P., Stauffer, Shaun R., and Fesik, Stephen W. Mon . "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". United States. https://doi.org/10.1021/acs.jmedchem.8b00375. https://www.osti.gov/servlets/purl/1499757.
@article{osti_1499757,
title = {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},
author = {Wang, Feng and Jeon, Kyu Ok and Salovich, James M. and Macdonald, Jonathan D. and Alvarado, Joseph and Gogliotti, Rocco D. and Phan, Jason and Olejniczak, Edward T. and Sun, Qi and Wang, Shidong and Camper, DeMarco and Yuh, Joannes P. and Shaw, J. Grace and Sai, Jiqing and Rossanese, Olivia W. and Tansey, William P. and Stauffer, Shaun R. and Fesik, Stephen W.},
abstractNote = {WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. In this a paper, we describe the discovery of potent and selective WDR5-WINsite inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5$H$pyrrolo[1,2-$a$]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.},
doi = {10.1021/acs.jmedchem.8b00375},
journal = {Journal of Medicinal Chemistry},
number = 13,
volume = 61,
place = {United States},
year = {Mon Jun 11 00:00:00 EDT 2018},
month = {Mon Jun 11 00:00:00 EDT 2018}
}

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Works referencing / citing this record:

Targeting WDR5: A WINning Anti-Cancer Strategy?
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