Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders

Abstract

WD40-repeat (WDR) domain proteins play a crucial role in mediating protein–protein interactions that sustain oncogenesis in human cancers. One prominent example is the interaction between the transcription factor MYC and its chromatin co-factor, WD40-repeat domain protein 5 (WDR5), which is essential for oncogenic processes. The MYC family of proteins is frequently overexpressed in various cancers and has been validated as a promising target for anticancer therapies. The recruitment of MYC to chromatin is facilitated by WDR5, highlighting the significance of their interaction. Consequently, inhibiting the MYC–WDR5 interaction has been shown to induce the regression of malignant tumors, offering an alternative approach to targeting MYC in the development of anticancer drugs. WDR5 has two protein interaction sites, the “WDR5-binding motif” (WBM) site for MYC interaction and the histone methyltransferases SET1 recognition motif “WDR5-interacting” (WIN) site forming MLL complex. Significant efforts have been dedicated to the discovery of inhibitors that target the WDR5 protein. More recently, the successful application of targeted protein degradation technology has enabled the removal of WDR5. This breakthrough has opened up new avenues for inhibiting the interaction between WDR5 and the binding partners. In this review, we address the recent progress made in targeting WDR5 to inhibit MDR5–MYC and MDR5–MLL1 interactions, including its targeted protein degradation and their potential impact on anticancer drug discovery.

Genome-Wide Identification, Evolution, and Expression Analysis of the WD40 Subfamily in Oryza Genus

“…Typically, the WD40 domain has a β-propeller structure containing 4-9 blades, and its scaffold-type structure can serve as an interaction site for a variety of biomolecules, including proteins, peptides, RNA, and DNA, which helps proteins exert their biological activities [4][5][6]. WD40 proteins have complex structures and functions; they can interact with diverse proteins in various ways and are involved in many bioregulatory processes such as DNA replication, damage response, transcriptional regulation, post-translational modification, signal transduction, and apoptosis [7][8][9][10]. In addition, most WD40 proteins are found in eukaryotes, and only a small fraction is found in prokaryotes [11].…”

A resource to enable chemical biology and drug discovery of WDR Proteins

“…2c, Table S7 ), which we believe is a conservative estimate considering that pockets are sometimes occluded in the absence of ligands. For example, the central pocket of the apo structure of EED is occluded by several residues which are displaced by binding of drug-like small molecule ligands 10,35 . The diversity in shape and electrostatics of the central pocket was striking 36,37 .…”

“…2b, Table S8 ), 17 of which had no reported small molecule ligands at the start of this program. WDR5 was included in the screen as a positive control, as it is druggable and has elicited clinical interest in the context of treating leukemias 6,8,35 . Given the novelty of the WDR family as a target class, we also included the PWWP domain of DNMT3A and the triple Tudor domain (TTD) of SETDB1 as two unrelated PPI domains that have been shown to be ligandable 38-40 .…”

“…As such, all hits comprise chemical templates that are readily amenable to structure-activity exploration and structural optimization ( Tables 1, S10 ). For example, a novel chemotype was discovered for the highly druggable WDR5 35 . Of 64 ML-predicted compounds, nine had SPR K D values less than 100 μM with some SAR ( Table S10 ).…”

Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

“…19,20,38 Overexpression of WDR5 has been reported in various cancers including leukemia, breast, lung, and bladder cancers. 39 Although no active site directed inhibitor of MLL1 has been reported, attempts to inhibit its methyltransferase activity by antagonizing its interaction with WDR5 resulted in the discovery of MM-401, a macrocyclic peptidomimetic that binds to the Win site of WDR5, 23 and other small molecule antagonists of WDR5-MLL interactions. 21,22,[24][25][26]29 Various effects of these compounds on cancers have been evaluated.…”