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

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based desig...

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Published inJournal of medicinal chemistry Vol. 61; no. 13; pp. 5623 - 5642
Main Authors 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
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 12.07.2018
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
HIGH-AFFINITY
COMPLEX
LINEAGE
BINDING
WD REPEAT
LEUKEMIA MLL PROTEIN
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Summary:WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site 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-5H-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.
Bibliography:Present Addresses: F.W.: Novartis Institutes for Biomedical Research, CA, USA; Q.S.: AbbVie, IL, USA; S.W.: Cell Signaling Technology, MA, USA; D.C.: Bristol-Meyers Squibb, MA, USA; O.W.R.: The Institute of Cancer Research, London, UK
F.W. and K.O.J. contributed equally to this work. All authors have given approval to the final version of the manuscript.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00375