Targeting WD Repeat-Containing Protein 5 (WDR5): A Medicinal Chemistry Perspective

Abstract

WD repeat-containing protein 5 (WDR5) is a member of the WD40 protein family, and it is widely involved in various biological activities and not limited to epigenetic regulation in vivo. WDR5 is also involved in the initiation and development of many diseases and plays a key role in these diseases. Since WDR5 was discovered, it has been suggested as a potential disease treatment target, and a large number of inhibitors targeting WDR5 have been discovered. In this review, we discussed the development of inhibitors targeting WDR5 over the years, and the biological mechanisms of these inhibitors based on previous mechanistic studies were explored. Finally, we describe the development potential of inhibitors targeting WDR5 and prospects for further applications.

Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization

“…General Procedure E was followed using 49 (30 mg, 0.062 mmol, 1 equiv), (2,5-dimethylpyridin-4yl)boronic acid (19 mg, 0.12 mmol, 2 equiv), potassium carbonate (21 mg, 0.15 mmol, 2.5 equiv), and PdCl 2 (dppf)•CH 2 Cl 2 (2.5 mg, 0.003 mmol, 0.05 equiv) to obtain the title compound (12 mg, 0.023 mmol, 38% yield). 1 (10). General Procedure E was followed using 49 (30 mg, 0.062 mmol, 1 equiv), (3-methylisoxazol-4-yl)boronic acid (16 mg, 0.12 mmol, 2 equiv), potassium carbonate (21 mg, 0.15 mmol, 2.5 equiv), and PdCl 2 (dppf)•CH 2 Cl 2 (2.5 mg, 0.003 mmol, 0.05 equiv) to obtain the title compound (13.3 mg, 0.027 mmol, 44% yield).…”

“…WDR5 is tethered to chromatin via the WIN site and recruits MYC to chromatin at tumor-critical target genes via a direct interaction of the WBM site of WDR5 with the conserved MYC Box IIIb element of MYC. − A MYC mutant, with impaired binding to WDR5, thus exhibits reduced binding of MYC to chromatin and loss of oncogenic potential in vivo , further supporting the role of WDR5 as a critical cofactor for MYC proteins in malignant gene expression programs . In addition, aberrant overexpression of WDR5 can be found in a variety of aggressive cancers including bladder, breast, colorectal, gastric, pancreatic, prostate, , neuroblastoma, head neck squamous cell carcinoma, liver, and various leukemias, , and is often associated with poor prognoses. ,, Therefore, inhibition of WDR5’s multifaceted role in human malignancies has emerged as an attractive potential anticancer therapy. ,,, The activity of WDR5 WIN site inhibition is mediated by displacement of WDR5 from chromatin at ribosomal protein genes (RPGs), which leads to an induction of nucleolar stress and activation of p53-dependent apoptosis. , The small-molecule-mediated displacement of WDR5 also displaced the oncoprotein transcription factor MYC at these same RPGs, highlighting that MYC proteins may be one source of multi-factorial vulnerability to these agents. , …”

“…WD repeat domain 5 (WDR5) is a highly conserved member of the WD40-repeat protein family with a characteristic circular barrel-shaped 7-bladed β-propeller structure. − WDR5 is a core scaffolding component that contains two major binding interfaces, the WDR5 binding motif (WBM) and WDR5 interaction motif (WIN) sites, on opposite sides to accommodate a large variety of partner proteins to form multiple protein complexes that are essential in a wide range of biological activities, most of which occur in the nucleus. − WDR5 has been extensively studied for its role in the activity of MLL1 histone methyltransferase (HMT) complexes, in which MLL1 binds on the WIN site using a conserved arginine in the MLL/SET proteins as an anchor. − ,,− The complex also contains at least three other evolutionarily conserved proteins (retinoblastoma binding protein 5 (RBBP5), ASH2L, and DPY30) binding through WIN-site-independent interactions and catalyzes histone H3 lysine 4 (H3K4) di- and tri-methylation (H3K4me2, me3). , All other MLL / SET (MLL2–4, SETd1A, and SETd1B) family proteins can form similar assemblies by engaging WDR5 on the WIN site through the same interactions but are less dependent on this interaction for catalytic activity than MLL1. ,− In addition, WDR5-containing nonspecific lethal (NSL) and Ada2-containing (ATAC) histone acetyltransferase (HAT) complexes carry out acetylation of histone H4 at lysine 16 (H4K16) …”

“…22,29,32 Therefore, inhibition of WDR5's multifaceted role in human malignancies has emerged as an attractive potential anticancer therapy. 4,10,18,33 The activity of WDR5 WIN site inhibition is mediated by displacement of WDR5 from chromatin at ribosomal protein genes (RPGs), which leads to an induction of nucleolar stress and activation of p53dependent apoptosis. 34,35 The small-molecule-mediated displacement of WDR5 also displaced the oncoprotein transcription factor MYC at these same RPGs, highlighting that MYC proteins may be one source of multi-factorial vulnerability to these agents.…”

Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction

“…6−9 For all direct WDR5 binding partners that have been studied in details, the interactions occur through either the WIN or the WBM sites, two opposite sides on this protein with donutshaped structure formed by β-propeller domains. 1 Most early drug discovery efforts centered on the WIN site of WDR5 since it was first best characterized as a core scaffolding component of histone methyltransferase MLL1 complex which showed genetic alterations in leukemias, 10,11 but emerging evidence demonstrate that it has other functions such as recruiting MYC to its target genes. 12,13 Thus, there is also an interest in targeting this MYC interacting WBM interface on WDR5 to regulate the association of MYC oncoprotein transcription factor with chromatin.…”