Discovery of WD Repeat-Containing Protein 5 (WDR5)–MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design
Open accessAbstract
The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5–MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5–MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.
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Chacon Simon et al. identified several other compound fragments via NMR fragment screening, resulting in compound (171) (IC50 = 100 nM).
“To address this, Chacon Simon et al. identified several other compound fragments via NMR fragment screening, resulting in compound (171) (IC50 = 100 nM).429”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [429]
Compound (171) is now being used to study the biological effects of the Myc-WDR5 complex.
“This compound is now being used to study the biological effects of the Myc-WDR5 complex.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [429]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Chacón Simon, S., Wang, F., Thomas, L. R., Phan, J., Zhao, B., Olejniczak, E. T., Macdonald, J. D., Shaw, J. G., Schlund, C., Payne, W., Creighton, J., Stauffer, S. R., Waterson, A. G., Tansey, W. P., & Fesik, S. W.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Fesik, Stephen W.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-03-30
- Volume
- 63
- Issue
- 8
- Pages
- 4315-4333
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7187413
- OpenAlex
- W3013483271
- Cited by
- 76
- References
- 37
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 18 · 2023: 17 · 2022: 7 · 2021: 19 · 2020: 1
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- National Cancer Institute (CA200709, CA211305, CA236733)
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- Edward P. Evans Foundation
- T.J. Martell Foundation
- Alex's Lemonade Stand Foundation for Childhood Cancer
- St. Baldrick’s Foundation
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- WDR5, c-Myc, small molecule inhibitors, fragment screening, structure-based drug design, sulfonamide derivatives, anticancer drug discovery
- MeSH terms
- Humans, Structure-Activity Relationship, Sulfonamides, Drug Design, Proto-Oncogene Proteins c-myc, Protein Structure, Tertiary, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Drug Discovery, HEK293 Cells
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