A new form of chemotherapy for leukemia

A team led by researchers at UC Santa Barbara and collaborators from UC San Francisco and Baylor College of Medicine have identified two compounds

Norbert Reich, a distinguished professor at the University of California, Santa Barbara, corresponding author of the study, said: "Our study of a mutant enzyme in leukemia patients has found a completely new way to regulate this enzyme and a new molecule

Epigenome

All cells in your body contain the same DNA or genome, but each cell uses a different blueprint section

The epigenome of a cell is replicated and preserved by an enzyme called DNMT1, a protein

However, even in adults, some cells need to differentiate into different kinds of cells

This all went well until something went wrong with DNMT3A, causing the bone marrow to turn into abnormal blood cells

Toxic treatment

Most anti-cancer drugs are designed to selectively kill cancer cells without harming healthy cells

Unfortunately, the active site of DNMT3A is actually the same as DNMT1, so the drug shuts down epigenetic regulation of all 30-40 trillion cells in patients

Blocking the active part of the protein is a direct way

Work together

When the team was studying DNMT3A, they noticed something strange

Early work in Reich's lab, led by former graduate student Celeste Holz-Schietinger, showed that disrupting complexes by mutation does not affect their ability

Around the same time, the New England Journal of Medicine conducted an in-depth study of mutations in leukemia patients

Discover new therapies

Reich and his team became interested

What's more, the two drugs don't bind to the active site of the protein, so they don't affect DNMT1

These drugs aren't just a potential breakthrough

This achievement will not be easy

The two compounds discovered by the team have been used in the clinical treatment
of other diseases.
This eliminates much of the cost, testing and bureaucracy required to develop leukemia therapies
.
In fact, oncologists can prescribe these drugs
to patients now.

Success on the basis of

However, there is much more to be learned about this new approach
.
The team hopes to learn more about how protein-protein inhibitors affect the DNMT3A complex in healthy bone marrow cells
.
Reich collaborated
with Tom Pettus, a chemistry professor at the University of California, Santa Barbara, and their co-phD student Ivan Hernandez.
"We're making changes to the drug to see if we can further improve selectivity and potency
," Reich said.

We need to learn more
about the long-term effects of these drugs.
Since these compounds act directly on enzymes, they may not alter the underlying mutations
that cause cancer.
This warning affects how doctors use these drugs
.
"One way is for patients to continue to receive low-dose treatment
," Reich said.
"Or, our approach could be used for other treatments, perhaps reducing the tumor burden to the point of
stopping treatment.
"

Reich also acknowledges that they have not yet studied the long-term effects
of PPIs on bone marrow differentiation.
They wondered if the drugs could trigger some type of cellular memory that would alleviate problems
at epigenetic or genetic levels.

That said, Reich was thrilled
by their findings.
"By not targeting the active site of DNMT3A, we have far exceeded the drug dicitabine currently in use, which is certainly cytotoxic
," he said.
He added that this approach could also be tailored to other cancers
.

Journal Reference:

1. Jonathan E.
   Sandoval, Raghav Ramabadran, Nathaniel Stillson, Letitia Sarah, Danica Galonić Fujimori, Margaret A.
   Goodell, Norbert Reich.
   First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein– Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation.
   Journal of Medicinal Chemistry, 2022; 65 (15): 10554 DOI: 10.
   1021/acs.
   jmedchem.
   2c00725