Scientists are developing a better type of chemotherapy

Researchers have found two compounds that are more potent and less toxic than existing leukemia treatments, which often cause unpleasant side effects in patients.

Researchers are discovering a new class of drugs that offer leukemia patients a safer, more targeted form of treatment.

Chemotherapy is no fun. It’s no secret that the drugs used in treatments often have harmful side effects on the patient and their cancer. Since tumors grow so quickly, the theory is that chemotherapy will eradicate the disease before its adverse effects take the life of the patient. For this reason, researchers and medical professionals are always looking for more effective treatments.

Researchers from the University of California, Santa Barbara, along with colleagues from the University of California, San Francisco and Baylor College of Medicine, have discovered two compounds that are both more potent and less toxic than current therapies for cancer. leukemia. The molecules work in a way that differs from conventional cancer treatments and may form the basis of an entirely new class of drugs.

Additionally, the compounds are already approved for the treatment of other diseases, greatly reducing the amount of paperwork required to modify them for the treatment of leukemia or even to administer them off-label. The results were recently published in the Journal of Medicinal Chemistry.

“Our work on an enzyme that is mutated in leukemia patients has led to the discovery of an entirely new way to regulate this enzyme, as well as new molecules that are more efficient and less toxic to human cells,” said the professor emeritus at UC Santa Barbara. Norbert Reich, the corresponding author of the study.

DNMT3A enzymes

A pair of DNMT3A enzymes joins two helper proteins (green) to form a four-part complex that moves along DNA adding chemical tags that tell a cell which genes to express. Credit: Jonathan Sandoval et al.

The epigenome

Although every cell in your body has the same DNA, or genome, depending on what type of cell it is, each uses a different part of this blueprint. This allows different cells to perform their specific tasks while using the same instruction manual; in reality, they just use different sections of it. The epigenome tells cells how to follow these instructions. Chemical markers, for example, control which sections are read and therefore dictate the actual fate of a cell.

A cell’s epigenome is copied and preserved by an enzyme (a type of protein) called DNMT1. This enzyme ensures, for example, that a dividing liver cell becomes two liver cells and not one brain cell.

However, even in adults, some cells have to differentiate into different cell types than they did before. For example, bone marrow stem cells are able to form all different types of blood cells, which do not reproduce on their own. This is controlled by another enzyme, DNMT3A.

All is well until something goes wrong with DNMT3A causing the bone marrow to turn into abnormal blood cells. It is a primary event leading to various forms of leukemia, as well as other cancers.

Toxic treatments

Most cancer drugs are designed to selectively kill cancer cells while leaving healthy cells alone. But it is extremely difficult, which is why so many of them are extremely poisonous. Current leukemia treatments, such as decitabine, bind to DNMT3A in a way that deactivates it, thereby slowing disease progression. They do this by obstructing the active site of the enzyme (essentially, its business activity) to prevent it from performing its function.

Unfortunately, the active site of DNMT3A is virtually identical to that of DNMT1, so the drug shuts down epigenetic regulation in all 30-40 trillion cells in the patient. This leads to one of the biggest bottlenecks in the pharmaceutical industry: off-target toxicity.

Obstructing the active site of a protein is an easy way to knock it offline. That’s why the active site is often the first place drug designers look when designing new drugs, Reich explained. However, about eight years ago he decided to investigate compounds that could bind to other sites to avoid off-target effects.

Work together

As the group investigated DNMT3A, they noticed something peculiar. While most of these epigenetic-related enzymes function alone, DNMT3A has always formed complexes, either with itself or with partner proteins. These complexes can involve more than 60 different partners and, interestingly, they act as guidance devices to direct DNMT3A to control particular genes.

Early work in the Reich lab, led by former graduate student Celeste Holz-Schietinger, showed that disrupting the complex with mutations did not interfere with its ability to add chemical markers to DNA. However, DNMT3A behaved differently when singly or in a single pair; it was not about staying on the DNA and marking one site after another, which is essential for its normal cellular function.

Around the same time, the New England Journal of Medicine conducted an extensive analysis of the mutations present in leukemia patients. The authors of this study found that the most common mutations in patients with acute myeloid leukemia are in the DNMT3A gene. Surprisingly, Holz-Schietinger had studied the exact same mutations. The team now had a direct link between DNMT3A and epigenetic changes leading to acute myeloid leukemia.

Discover a new treatment

Reich and his group were interested in identifying drugs that could interfere with the formation of DNMT3A complexes that occur in cancer cells. They obtained a chemical library containing 1,500 previously studied drugs and identified two that disrupt DNMT3A’s interactions with partner proteins (protein-protein inhibitors or PPIs).

Furthermore, these two drugs do not bind to the active site of the protein, so they do not affect DNMT1 at work in all other cells in the body. “This selectivity is exactly what I hoped to discover with the students on this project,” Reich said.

These drugs are more than just a potential breakthrough in the treatment of leukemia. These are a whole new class of drugs: protein-protein inhibitors that target a part of the enzyme away from its active site. “An allosteric PPI has never been done before, at least not for an epigenetic drug target,” Reich said. “It really made me smile when we got the result.”

This achievement is no small feat. “Developing small molecules that disrupt protein-protein interactions has proven challenging,” noted lead author Jonathan Sandoval of UC San Francisco, a former doctoral student in Reich’s lab. “These are the first reported inhibitors of DNMT3A that disrupt protein-protein interactions.”

The two compounds identified by the team have already been used clinically for other diseases. This eliminates a lot of the cost, testing, and bureaucracy involved in developing them into leukemia therapies. In fact, oncologists could prescribe these drugs to off-label patients now.

Building on success

There’s still more to understand about this new approach, however. The team wants to learn more about how protein-protein inhibitors affect DNMT3A complexes in healthy bone marrow cells. Reich is collaborating with UC Santa Barbara chemistry professor Tom Pettus and one of their doctoral students, Ivan Hernandez. “We are making changes to the drugs to see if we can further improve selectivity and potency,” Reich said.

There is also more to learn about the long-term effects of medications. Since the compounds act directly on enzymes, they might not alter the underlying cancer-causing mutations. This warning affects how doctors can use these drugs. “One approach is for a patient to continue on low doses,” Reich said. “Alternatively, our approach could be used with other treatments, perhaps to reduce tumor burden to a point where stopping treatment is an option.”

Reich also admits that the team has yet to learn what effect PPIs have on long-term bone marrow differentiation. They are curious whether drugs can elicit some type of cellular memory that could alleviate problems at the epigenetic or genetic level.

That said, Reich is excited about their discovery. “By not targeting the active site of DNMT3A, we are already miles beyond the currently used drug, decitabine, which is definitely cytotoxic,” he said, adding that this type of approach could also be suitable for other cancers.

Reference: “First-class allosteric inhibitors of DNMT3A disrupt protein-protein interactions and induce cellular differentiation in acute myeloid leukemia” by Jonathan E. Sandoval, Raghav Ramabadran, Nathaniel Stillson, Letitia Sarah, Danica Galonić Fujimori, Margaret A. Goodell and Norbert Reich, July 22, 2022, Journal of Medicinal Chemistry.
DOI: 10.1021/acs.jmedchem.2c00725

Comments are closed.