WDR5 (WD repeat-containing protein 5) is a protein that regulates gene activity within cells. Inhibiting specific proteins like WDR5 can significantly influence biological processes, offering new avenues for therapeutic development. This approach, which blocks or reduces protein activity to restore cellular balance, is gaining considerable interest in medicine.
Understanding WDR5 and Its Biological Role
WDR5 functions as a core component of the mixed-lineage leukemia (MLL) or COMPASS complexes. These multi-protein assemblies modify histones, the proteins around which DNA is wrapped within the cell nucleus. Specifically, WDR5 is involved in the methylation of histone H3 at lysine 4 (H3K4). This histone methylation, including H3K4 trimethylation (H3K4me3), is an epigenetic modification that influences how genes are expressed.
H3K4 methylation is associated with active gene transcription. WDR5 facilitates this by presenting the histone H3 substrate to MLL methyltransferase enzymes. This interaction is important for the MLL complexes’ enzymatic activity, which is otherwise low. By influencing H3K4 methylation, WDR5 regulates gene expression involved in normal cellular functions, development, and disease.
What WDR5 Inhibitors Are
WDR5 inhibitors are molecules designed to interfere with the normal functions of the WDR5 protein. These inhibitors are often small molecules, simple chemical compounds that interact with proteins. Their purpose is to prevent WDR5 from participating in its cellular processes, especially gene regulation.
The development of WDR5 inhibitors stems from understanding that aberrant WDR5 activity can contribute to disease. By blocking WDR5, these compounds aim to disrupt pathways overactive or improperly regulated in pathological conditions. Their design focuses on achieving specificity to primarily affect WDR5 while minimizing off-target effects.
How WDR5 Inhibitors Function
WDR5 inhibitors exert their effects by binding to specific sites on the WDR5 protein. One well-characterized target is the “WIN” (WDR5-interacting) site, an arginine-binding cavity. This site is where WDR5 normally binds to an arginine-containing motif within MLL proteins, an interaction necessary for the MLL complex’s histone H3K4 dimethylation activity.
When an inhibitor binds to the WIN site, it prevents WDR5 from interacting with MLL or other partner proteins that utilize this binding pocket. This disruption can impede the assembly and stability of the MLL/COMPASS complex, reducing its ability to catalyze H3K4 methylation. By interfering with this process, WDR5 inhibitors can change gene expression patterns, reversing abnormal gene activation that contributes to disease progression. Some inhibitors may also displace WDR5 from chromatin, affecting associated gene expression and leading to translational inhibition.
WDR5 Inhibitors in Disease Investigation
WDR5 inhibitors are being investigated for their therapeutic applications, particularly in cancer. WDR5 is dysregulated in many human cancers, making it an appealing target. A focus area is leukemias, such as MLL-rearranged leukemias, where MLL fusion proteins drive disease. In these cancers, inhibiting WDR5 can reduce H3K4 trimethylation and suppress oncogenic gene expression, leading to cancer cell growth inhibition, cell cycle arrest, and programmed cell death.
Beyond leukemias, WDR5 inhibitors are promising in solid tumors and other hematologic malignancies. Research indicates their activity against a range of cancer cell types, including those with p53 gene mutations. Inhibiting WDR5 in these diseases reverses abnormal gene expression that fuels tumor growth and progression, affecting pathways like ribosomal protein gene transcription and inducing cellular stress responses.
The Journey of WDR5 Inhibitor Development
The development of WDR5 inhibitors follows a multi-stage pipeline, starting with drug discovery. This phase involves identifying lead compounds through high-throughput screening or structure-based design that bind to and inhibit WDR5 activity. Researchers aim for molecules with high potency and specificity for WDR5.
Once promising compounds are identified, they proceed to preclinical testing. This stage evaluates efficacy and safety in laboratory settings, using cell lines and animal models. These tests assess how well inhibitors reduce cancer cell proliferation or tumor growth and identify toxic effects. Compounds demonstrating favorable preclinical properties advance to early-phase clinical trials (Phase 1 or 2) to evaluate safety, dosage, and initial efficacy.