6U80

Discovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction

6U80 の概要

• エントリーDOI: 10.2210/pdb6u80/pdb
• 分子名称: WD repeat-containing protein 5, 5-bromo-N-(4-hydroxy[1,1'-biphenyl]-3-yl)-2-methoxybenzene-1-sulfonamide (3 entities in total)
• 機能のキーワード: wdr5, myc, rbbp5, structure-based design, high-throughput screening, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69334.29

構造登録者

Zhao, B.,Wang, F. (登録日: 2019-09-04, 公開日: 2019-12-04, 最終更新日: 2023-10-11)

主引用文献

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

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: 31724864
DOI: 10.1021/acs.jmedchem.9b01411

実験手法

X-RAY DIFFRACTION (1.55 Å)