Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction
Open accessAbstract
The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.
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Compound (170) was the most active (IC50 = 29 nM) but was unsuitable for in vivo studies.
“Although compound (170) was the most active (IC50 = 29 nM), it was unsuitable for in vivo studies.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [428]
In 2019, Macdonald et al. discovered a class of Myc-WDR5 inhibitors with a sulfonamide structure via high-throughput screening (HTS).
“In 2019, Macdonald et al. discovered a class of Myc-WDR5 inhibitors with a sulfonamide structure via high-throughput screening (HTS).428”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [428]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Macdonald, J. D., Chacón Simon, S., Han, C., Wang, F., Shaw, J. G., Howes, J. E., Sai, J., Yuh, J. P., Camper, D., Alicie, B. M., Alvarado, J., Nikhar, S., Payne, W., Aho, E. R., Bauer, J. A., Zhao, B., Phan, J., Thomas, L. R., Rossanese, O. W., Tansey, W. P., Waterson, A. G., Stauffer, S. R., & Fesik, S. W.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Fesik, Stephen W.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-11-14
- Volume
- 62
- Issue
- 24
- Pages
- 11232-11259
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6933084
- OpenAlex
- W2988685436
- Cited by
- 66
- References
- 55
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 18 · 2023: 16 · 2022: 4 · 2021: 10 · 2020: 2 · 2019: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- National Cancer Institute (CA200709)
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- Edward P. Evans Foundation
- Alex's Lemonade Stand Foundation for Childhood Cancer
- T. J. Martell Foundation
- St. Baldrick?s Foundation
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- c-Myc, WDR5, protein-protein interaction inhibitors, small molecule inhibitors, salicylates, sulfonamides, MYC-driven tumors, structure-based drug design, high-throughput screening, negative control
- MeSH terms
- WD40 Repeats, DNA-Binding Proteins, Humans, Protein Binding, Protein Conformation, Sulfonamides, Proto-Oncogene Proteins c-myc, Salicylic Acid, Intracellular Signaling Peptides and Proteins, Protein Interaction Domains and Motifs, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays, HEK293 Cells
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