A PRMT5 inhibitor is a compound or drug designed to block the activity of the enzyme Protein Arginine Methyltransferase 5 (PRMT5). This enzyme modifies proteins through methylation, influencing various cellular processes. By hindering PRMT5’s function, these inhibitors disrupt specific biological pathways. They are a focus in medical research due to their potential to treat diseases where PRMT5 activity is abnormally high or dysregulated.
Understanding PRMT5
PRMT5 is an enzyme. It functions as a type II arginine methyltransferase, adding methyl groups to specific arginine residues on various proteins, including histones and non-histone proteins. This modification, symmetric dimethylation, influences protein characteristics and functions.
PRMT5 participates in many biological functions, such as gene regulation, protein synthesis, and cell growth. For instance, it contributes to the development and differentiation of oligodendrocyte progenitor cells, which are responsible for myelin production, by adding methylation marks on histones H4R3. Its activity also affects cellular processes like chromatin regulation, RNA splicing, DNA damage response, and cell signaling, which are all important for maintaining normal cell functions.
Why Target PRMT5?
While PRMT5 is a normal and necessary protein, its activity can become dysregulated in certain disease states. This abnormal activity is frequently observed in various cancers, including leukemias, lymphomas, and solid tumors like those in the lung, colon, breast, and pancreas. In these conditions, elevated PRMT5 expression links to uncontrolled cell growth, increased cell survival, and enhanced proliferation.
The dysregulation of PRMT5 contributes to tumor progression by influencing epigenetic regulation of gene expression, RNA splicing, and signal transduction pathways. For example, PRMT5 can repress tumor suppressor genes by methylating histones in their promoter regions, thereby promoting cell proliferation. Its overexpression has also been tied to cellular transformation and reduced cell death, making it an appealing therapeutic target in cancer and other conditions where its activity is abnormally high.
How PRMT5 Inhibitors Work
PRMT5 inhibitors function by binding to the PRMT5 enzyme, preventing it from carrying out its enzymatic activity. This involves blocking the transfer of methyl groups from S-adenosylmethionine (SAM) to target arginine residues on substrate proteins. By inhibiting this methylation, these compounds disrupt abnormal pathways that contribute to disease progression.
Different types of PRMT5 inhibitors exist, each with a varied mechanism or binding site. Some inhibitors are competitive; they directly compete with SAM for binding to the enzyme’s active site. Other inhibitors are allosteric, binding to a different site on the enzyme and inducing changes that reduce its activity. This inhibition leads to effects within the cell, such as halting cancer cell growth or inducing cell death, by modulating the methylation status of PRMT5 substrates.
Current Research and Therapeutic Potential
Research into PRMT5 inhibitors is progressing, with many compounds in preclinical and clinical trials. Over 10 PRMT5 inhibitors have entered clinical trials for cancer therapy, primarily in Phase I. These inhibitors show promise in various cancers, including adenoid cystic carcinoma, where partial responses have been observed.
A notable development is the emergence of second-generation PRMT5 inhibitors, designed to selectively target cancer cells with a genetic alteration called MTAP deletion. This deletion, found in 10-15% of human cancers, leads to an accumulation of the metabolite methylthioadenosine (MTA), making these cells more vulnerable to PRMT5 inhibition. These newer inhibitors suppress PRMT5 activity specifically in MTAP-null cells while sparing healthy cells, potentially reducing side effects like bone marrow toxicity seen with earlier inhibitors. For example, a potent and blood-brain barrier penetrant PRMT5 inhibitor is being investigated for MTAP-deleted glioblastoma and non-small cell lung cancer, showing greater potency in MTAP-deleted cancer cells compared to normal cells in preclinical studies.