Researchers discover a new class of medications that offer a safer treatment for leukemia

According to a press release, researchers from the University of California, Santa Barbara, University of California, San Francisco, and Baylor College of Medicine discovered two molecules that are more potent and less toxic than conventional leukemia treatments. Traditional treatments can lead to undesirable side effects on both the patient and their cancer.

The two molecules, which are already approved for treating other diseases, work differently from present-day cancer treatments, and could be the basis for an entirely new class of medications.

“Our work on an enzyme that is mutated in leukemia patients has led to 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 corresponding author of the study.

A cell’s epigenome

A cell’s epigenome is copied and maintained by an enzyme called DNMT1. For instance, this enzyme ensures that a dividing liver cell produces two liver cells rather than a brain cell.

However, some cells need to undergo differentiation to become new types of cells. For instance, bone marrow stem cells can develop all the various blood cell types, which are incapable of self-replication. DNMT3A, another enzyme, manages this.

This is not a problem until a dysfunction of DNMT3A results in the production of abnormal blood cells from bone marrow. This is a prominent factor in the development of several types of leukemia as well as other cancers.

Most cancer medications are intended to attack cancer cells while only leaving healthy cells. But this is quite a challenging process; therefore, most have severe side effects.

Current leukemia medications, such as Decitabine, bind to DNMT3A in a way that disables it. So that they slow the progression of the disease by obstructing the enzyme's active site, preventing it from continuing its function.

Unfortunately, the active site of DNMT3A is virtually identical to that of DNMT1, therefore, the medication blocks epigenetic regulation in patients' 30 to 40 trillion cells. This leads to off-target toxicity- one of the drug industry's largest bottlenecks.

Clogging the active site of a protein is a way of taking it offline. Because of this, the active site is frequently the first consideration for drug designers when creating new medications, Reich explained. To avoid off-target effects, he chose to look at substances that may bind to other places roughly eight years ago.

Two drugs that don't bind to the active site of a protein

During the investigation, the research group noticed that, unlike other epigenetic-related enzymes, DNMT3A always formed complexes, either with itself or with partner proteins and these complexes can involve more than 60 different partners.

The researchers worked on identifying drugs that could interfere with the formation of DNMT3A complexes that develop in cancer cells. They acquired a chemical library that contains 1,500 previously studied medicines and detected two drugs that disrupt the interactions of DNMT3A with partner proteins (protein-protein inhibitors, or PPIs).

Moreover, these two drugs don't bind to the active site of a protein. Therefore, they don’t affect the DNMT1 at work in all of the body’s other cells. “This selectivity is exactly what I was hoping to discover with the students on this project,” Reich said.

These drugs are more than merely a potential breakthrough in leukemia treatment. They are a completely new class of drugs: protein-protein inhibitors that don't target the active site of an enzyme.

“Developing small molecules that disrupt protein-protein interactions has proven challenging,” said lead author Jonathan Sandoval from the University of California, San Francisco, a former doctoral student in Reich’s lab. “These are the first reported inhibitors of DNMT3A that disrupt protein-protein interactions.”

There's still more to learn about this novel strategy, though. Researchers are looking to understand how DNMT3A complexes in healthy bone marrow cells are impacted by protein-protein inhibitors. There’s also more to learn about the drugs’ long-term effects. The substances may not alter the underlying mutations causing cancer since they impact directly on the enzymes.

The study was published in the Journal of Medicinal Chemistry.

Abstract:

We previously identified two structurally related pyrazolone (compound 1) and pyridazine (compound 2) allosteric inhibitors of DNMT3A through screening of a small chemical library. Here, we show that these compounds bind and disrupt protein–protein interactions (PPIs) at the DNMT3A tetramer interface. This disruption is observed with distinct partner proteins and occurs even when the complexes are acting on DNA, which better reflects the cellular context. Compound 2 induces differentiation of distinct myeloid leukemia cell lines including cells with mutated DNMT3A R882. To date, small molecules targeting DNMT3A are limited to competitive inhibitors of AdoMet or DNA and display extreme toxicity. Our work is the first to identify small molecules with a mechanism of inhibition involving the disruption of PPIs with DNMT3A. Ongoing optimization of compounds 1 and 2 provides a promising basis to induce myeloid differentiation and treatment of diseases that display aberrant PPIs with DNMT3A, such as acute myeloid leukemia.