6U8L
Discovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction
Summary for 6U8L
| Entry DOI | 10.2210/pdb6u8l/pdb |
| Descriptor | WD repeat-containing protein 5, 3-{[(5-bromo-2-hydroxyphenyl)sulfonyl]amino}-5-cyclopropyl-6-fluoro-2-hydroxybenzoic acid, N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]isoquinolin-1-amine, ... (4 entities in total) |
| Functional Keywords | wdr5, myc, rbbp5, structure-based design, high-throughput screening, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 68603.36 |
| Authors | |
| Primary citation | Macdonald, J.D.,Chacon 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. Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction. J.Med.Chem., 62:11232-11259, 2019 Cited by PubMed Abstract: 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. PubMed: 31724864DOI: 10.1021/acs.jmedchem.9b01411 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.57 Å) |
Structure validation
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