Screening and optimization of phage display cyclic peptides against the WDR5 WBM site

Song, Lingyu; Cao, Jiawen; Chen, Lin; Du, Zhiyan; Zhang, Naixia; Cao, Danyan; Xiong, Bing

doi:10.1039/d3md00288h

Cited by 1 publication

(1 citation statement)

References 41 publications

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“…A number of WBM site inhibitors have been discovered [ 14 , 19 , 20 , 21 ], but these have yet to progress sufficiently for thorough interrogation in cells or animal models. The discovery of WIN site inhibitors (WINi), in contrast, has been very successful (e.g., [ 1 , 2 , 15 , 16 , 17 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]), due in large part to the tractability of the WIN site and a deep understanding of structure–activity relationships in this class of agents.…”

Section: Strategies To Target Wdr5mentioning

confidence: 99%

WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think

Weissmiller,

Fesik,

Tansey

2024

JCM

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WDR5 is a conserved nuclear protein that scaffolds the assembly of epigenetic regulatory complexes and moonlights in functions ranging from recruiting MYC oncoproteins to chromatin to facilitating the integrity of mitosis. It is also a high-value target for anti-cancer therapies, with small molecule WDR5 inhibitors and degraders undergoing extensive preclinical assessment. WDR5 inhibitors were originally conceived as epigenetic modulators, proposed to inhibit cancer cells by reversing oncogenic patterns of histone H3 lysine 4 methylation—a notion that persists to this day. This premise, however, does not withstand contemporary inspection and establishes expectations for the mechanisms and utility of WDR5 inhibitors that can likely never be met. Here, we highlight salient misconceptions regarding WDR5 inhibitors as epigenetic modulators and provide a unified model for their action as a ribosome-directed anti-cancer therapy that helps focus understanding of when and how the tumor-inhibiting properties of these agents can best be understood and exploited.

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