According to a news release, scientists from Baylor College of Medicine, University of California, San Francisco, and University of California, Santa Barbara have found two molecules that are more effective & less toxic than standard leukemia treatments. The patient and their cancer may have negative side effects from conventional treatment.
The two molecules, which have already received approval for the treatment of other illnesses, operate differently from conventional cancer therapies and could be basis for an entirely new class of drugs.
“Our research on a mutated enzyme in leukemia patients has resulted in the discovery of an entirely new way of regulating this enzyme, as well as new molecules that are more effective and less toxic to human cells,” said Norbert Reich, a distinguished professor at the University of California, Santa Barbara and the study’s corresponding author.
A cell’s epigenome
An enzyme called DNMT1 copies and maintains a cell’s epigenome. This enzyme, for example, guarantees that a dividing liver cell creates 2 liver cells rather than one brain cell.
However, some cells require differentiation in order to change into new cell types. For instance, all the different types of blood cells, none of which are capable of self-replication, can be developed by bone marrow stem cells. Another enzyme, DNMT3A, controls this.
This isn’t a problem until DNMT3A deficiency causes the generation of ab-normal blood cells from bone marrow. This is a significant contributor to the development of various forms of leukemia as well as other cancers.
Most cancer treatments are designed to target cancer cells while leaving healthy cells alone. However, because this is a difficult process, most experience serious adverse effects.
Current leukemia treatments like Decitabine bind to DNMT3A in a way that disable-it. So that they impede the enzyme’s active site and stop it from continuing to function, which slows the disease’s progression.
Unfortunately, because the DNMT3A active site is nearly identical to the DNMT1 active site, the medicine inhibits epigenetic regulation in the 30-40 trillion cells of patients. Off-target toxicity results, which is one of the biggest bottlenecks in the pharmaceutical sector.
A protein can be turned off by clogging its active site. As a result, the active site is typically the first factor taken into account by drug designers when developing new drugs, according to Reich. He chose to look at compounds that may bind to other areas around eight years ago to avoid off-target consequences.
Two drugs that don’t bind to the active site of a protein
In contrast to other epigenetic-related enzymes, DNMT3A always forms complexes, either with itself or with partner proteins, and these complexes can involve more than 60 different partners, the research team discovered during their analysis.
The goal of the research was to find medications that could prevent the development of DNMT3A complexes in cancer cells. They purchased a chemical library of 1,500 previously researched compounds, and found two drugs that disrupt with the interactions of DNMT3A with partner proteins (protein-protein inhibitors, or PPIs).
Additionally, neither of these two medications bind to a protein’s active site. As a result, they have no effect on the DNMT1 that is active in all other cells in the body. With the help of the students on this project, I was specifically hoping to find this selectivity, Reich stated.
These medications represent more than just a potential advance in the treatment of leukemia. They are protein-protein inhibitors, which are a brand-new family of medications that don’t focus on an enzyme’s active site.
A doctoral student in Reich’s lab and main author Jonathan Sandoval of the University of California, San Francisco remarked, “Developing small molecules that disrupt protein-protein interactions has been tough.” These are the first DNMT3A inhibitors that have been reported to interfere with protein-protein interactions.
But there’s still a lot to learn about this cutting-edge tactic. Protein-protein inhibitors have an effect on DNMT3A complexes in healthy bone marrow cells, and this effect is being studied by researchers. The long-term effects of the medications also require further study. Because the drugs operate directly on the enzymes, they may not affect the underlying mutations that cause cancer.
The study was published in the Journal of Medicinal Chemistry.