Los científicos desarrollan un mejor tipo de quimioterapia

Los investigadores descubren una nueva clase de medicamentos que brindan a los pacientes con leucemia una forma de terapia más segura y más específica.

La quimioterapia no es divertida. No es ningún secreto que los medicamentos utilizados en los tratamientos a menudo tienen efectos secundarios dañinos tanto para el paciente como para el cáncer. Dado que los tumores crecen tan rápidamente, la teoría es que la quimioterapia erradicará la enfermedad antes de que sus efectos adversos se lleven la vida del paciente. Debido a esto, los investigadores y profesionales médicos siempre están buscando tratamientos que sean más efectivos.

Investigadores de la Universidad de California, Santa Bárbara, junto con colegas de la Universidad de California, San Francisco y la Facultad de Medicina de Baylor, han descubierto dos compuestos que son más potentes y menos tóxicos que las terapias actuales contra la leucemia. Las moléculas funcionan de una manera diferente a la de los tratamientos convencionales contra el cáncer y pueden servir como base para toda una nueva clase de medicamentos.

Además, los compuestos ya están aprobados para el tratamiento de otras enfermedades, lo que reduce significativamente la cantidad de trámites burocráticos necesarios para modificarlos para el tratamiento de la leucemia o incluso para administrarlos fuera de etiqueta. Los hallazgos fueron publicados recientemente en el Revista de Química Medicinal.

“Nuestro trabajo en una enzima que está mutada en pacientes con leucemia ha llevado al descubrimiento de una forma completamente nueva de regular esta enzima, así como nuevas moléculas que son más efectivas y menos tóxicas para las células humanas”, dijo el profesor distinguido de UC Santa Barbara. Norbert Reich, autor correspondiente del estudio.

Un par de enzimas DNMT3A se unen a dos proteínas auxiliares (verde) para formar un complejo de cuatro partes que viaja a lo largo del ADN agregando etiquetas químicas que le indican a una célula qué genes expresar. Crédito: Jonathan Sandoval et al.

el epigenoma

Aunque cada célula de su cuerpo tiene la misma[{” attribute=””>DNA, or genome, depending on the kind of cell it is, each one uses a different portion of this blueprint. This allows various cells to do their specific tasks while still utilizing the same instruction manual; in reality, they merely utilize different sections of it. The epigenome instructs cells on how to follow these directions. Chemical markers, for instance, control which sections are read and hence 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 turns into two liver cells and not a brain cell.

However, even in adults, some cells do need to differentiate into different kinds of cells than they were before. For example, bone marrow stem cells are capable of forming all the different blood cell types, which don’t reproduce on their own. This is controlled by another enzyme, DNMT3A.

This is all well and good until something goes wrong with DNMT3A, causing bone marrow to turn into abnormal blood cells. This 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 this is extremely challenging, which is why so many of them are extremely toxic. Current leukemia treatments, like Decitabine, bind to DNMT3A in a way that disables it, thereby slowing the progression of the disease. They do this by clogging up the enzyme’s active site (essentially, its business end) to prevent it from carrying out its function.

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

Clogging a protein’s active site is a straightforward way to take 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 in an effort to avoid off-target effects.

Working together

As the group was investigating DNMT3A, they noticed something peculiar. While most of these epigenetic-related enzymes work on their own, DNMT3A always formed complexes, either with itself or with partner proteins. These complexes can involve more than 60 different partners, and interestingly, they act as homing 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 through mutations did not interfere with its ability to add chemical markers to the DNA. However, the DNMT3A behaved differently when it was on its own or in a simple pair; it wasn’t to stay on the DNA and mark one site after another, which is essential for its normal cellular function.

Around the same time, the New England Journal of Medicine ran a deep dive into the mutations present in leukemia patients. The authors of that study discovered that the most frequent mutations in acute myeloid leukemia patients are in the DNMT3A gene. Surprisingly, Holz-Schietinger had studied the exact same mutations. The team now had a direct link between DNMT3A and the epigenetic changes leading to acute myeloid leukemia.

Discovering a new treatment

Reich and his group became 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 interactions with partner proteins (protein-protein inhibitors, or PPIs).

What’s more, these two drugs do not bind to the protein’s active site, so 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 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 put a smile on my face when we got the result.”

This achievement is no mean 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 the team identified have already been used clinically for other diseases. This eliminates a lot of costs, testing, and bureaucracy involved in developing them into leukemia therapies. In fact, oncologists could prescribe these drugs to patients off-label right now.

Building on success

There’s still more to understand about this new approach, though. 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 a joint doctoral student of theirs, Ivan Hernandez. “We are making changes in the drugs to see if we can improve the selectivity and potency even more,” Reich said.

There’s also more to learn about the drugs’ long-term effects. Because the compounds work directly on the enzymes, they might not change the underlying mutations causing the cancer. This caveat affects how doctors can use these drugs. “One approach is that a patient would continue to receive low doses,” Reich said. “Alternatively, our approach could be used with other treatments, perhaps to bring the tumor burden down to a point where stopping treatment is an option.”

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

That said, Reich is buoyed by their discovery. “By not targeting DNMT3A’s active site, we are already leagues beyond the currently used drug, Decitabine, which is definitely cytotoxic,” he said, adding that this type of approach could be tailored to other cancers as well.

Reference: “First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein-Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation” by Jonathan E. Sandoval, Raghav Ramabadran, Nathaniel Stillson, Letitia Sarah, Danica Galonić Fujimori, Margaret A. Goodell and Norbert Reich, 22 July 2022, Journal of Medicinal Chemistry.
DOI: 10.1021/acs.jmedchem.2c00725