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Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.

Ding J, Liu L, Chiang YL, Zhao M, Liu H, Yang F, Shen L, Lin Y, Deng H, Gao J, Sage DR, West L, Llamas LA, Hao X, Kawatkar S, Li E, Jain RK, Tallarico JA, Canham SM, Wang H
J Med Chem (2023)
Cited: 1 times
EuropePMC logo PMID: 37307526

Abstract

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound

Reviews citing this publication (1)

  1. WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think. Weissmiller AM, Fesik SW, Tansey WP. J Clin Med 13 274 (2024)


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