Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction
Autor: | Jason Phan, Olivia W. Rossanese, J.G. Shaw, Chao Han, Leiber Thomas, DeMarco V. Camper, Bin Zhao, Erin R. Aho, S.W. Fesik, Joseph Alvarado, J.A. Bauer, Feng Wang, Bethany M. Alicie, Joannes P. Yuh, Jennifer E. Howes, Jonathan David Macdonald, Sameer Nikhar, Jiqing Sai, William G. Payne, S. Chacon Simon, Alex G. Waterson, Shaun R. Stauffer, William P. Tansey |
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Rok vydání: | 2019 |
Předmět: |
WD40 Repeats
Protein Conformation Plasma protein binding 01 natural sciences Article Protein–protein interaction Proto-Oncogene Proteins c-myc Small Molecule Libraries 03 medical and health sciences Protein structure WD40 repeat Drug Discovery Humans Protein Interaction Domains and Motifs 030304 developmental biology 0303 health sciences Sulfonamides Chemistry Drug discovery WD Repeat-Containing Protein 5 HEK 293 cells Intracellular Signaling Peptides and Proteins 0104 chemical sciences Chromatin Cell biology High-Throughput Screening Assays DNA-Binding Proteins 010404 medicinal & biomolecular chemistry HEK293 Cells Molecular Medicine Salicylic Acid Protein Binding |
Zdroj: | Journal of medicinal chemistry. 62(24) |
ISSN: | 1520-4804 |
Popis: | 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. |
Databáze: | OpenAIRE |
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