Inhibiting an enzyme to drive melanoma drug development

Scientists at the Sanford Burnham Prebys Center (SBP) have shown for the first time that inhibition of the metabolic enzyme GCDH selectively kills melanoma cells and stops tumor growth. Those discoveriespublished in the magazine Nature Cell Biologymay lead to the development of new drugs to selectively treat this disease, the most serious form of skin cancer.

“We found that melanoma is addicted to the GCDH enzyme and that, if we inhibit it, changes are produced in a protein called NRF2 that acquires its ability to suppress cancer. Now, our goal is to find a drug, or several, that limit GCDH activity,” he explains. Ze’ev Ronaidirector of the SBP and co-author of the study.

Melanoma is addicted to the GCDH enzyme, and if we inhibit it, changes occur in a protein called NRF2 that acquires its ability to suppress cancer.

Ze’ev Ronai, SBP

The scientist tells SINC that he said medicines they will be based on “small molecules that can impede the activity of this metabolic enzyme, thus mimicking the changes observed after genetic inactivation. The molecules are selected based on their ability to increase the stability of NRF2 and kill cancer cells, among other criteria.”

The role of this enzyme

O Glutaryl-CoA Dehydrogenase GCDH plays an important role in the metabolism of lysine and tryptophan, essential amino acids for human health. When Ronai’s team began to discover how tumor cells generate energy from lysine, they discovered that the enzyme was essential in this process.

“The cells of this pathology feed on lysine and tryptophan to produce energy”, he says. Sachin Verma, first author of the study. “However, harnessing energy in this way requires cancer cells to remove the toxic waste produced during this six-step process. We therefore thought that cells would need all six enzymes, but it turns out that only one of them is crucial, GCDH, as melanoma cannot survive without it.”

GCDH plays an important role in the metabolism of lysine and tryptophan, essential amino acids for human health.

Further exploration showed that inhibition of this enzyme in an animal model conferred NRF2 cancer suppressing properties.

“We’ve known for a long time that this protein can be both a driver and a suppressor of cancer,” says Ronai. “We just didn’t know how to change NRF2 from a conductor to a suppressor function. the answer.”

A finding limited to melanoma

The researchers also found that the inhibition of Glutaryl-CoA Dehydrogenase was quite selective for melanoma tumors. Similar efforts in lung, breast and other cancers have had no impact, likely because these cancers can be addicted to other enzymes.

Similar efforts in lung, breast and other cancers have had no impact, likely because these cancers can be addicted to other enzymes.

“We didn’t evaluate other major types of skin cancer, such as basal cell or squamous cell, largely because they are caused by different genetic changes than those that cause melanoma,” says the director of the SBP cancer center.

To simulate the tumors of patients with this disease with a low level of Glutaryl-CoA Dehydrogenase, animal models lacking this enzyme, which could not tolerate a high-protein diet, were also taken into account. Given the role of the enzyme in protein processing, the authors believe that tumors low in GHCG may also be vulnerable to foods rich in these, which would allow them to establish a possible dietary treatment.

small molecules against cancer

As normal cells without GCDH are not affected, enzyme inhibitors would only act on melanoma cells. Ronai’s lab is now working with the Conrad Prebys Center for Chemical Genomics to identify small molecule inhibitors which may be the starting point for future treatments for this type of skin cancer.

Small molecules can selectively target tumor cells with little or no impact on non-cancerous tissues. It is expected that these inhibitors may act synergistically with other drugs.

Ze’ev Ronai, SBP

“These molecules can selectively target tumor cells with little or no impact on non-cancerous tissues. These inhibitors are expected to act synergistically with other drugs, which will offer a new therapeutic modality for the disease”, comments Ronai.

“In the study, we used genetic approaches to inhibit GCDH, which provide proof of concept for the search for small molecule inhibitors,” says Verma. “In fact, we’re actively looking for possible drugs that could deactivate this enzyme.”

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