Newly discovered molecule kills hard-to-treat cancers

The study was carried out in isolated cells, in human cancerous tissues and in human cancers cultured in mice.

The new compound called ERX-41 kills a wide range of hard-to-treat cancers.

A new molecule created by a University of Texas at Dallas researcher kills a variety of hard-to-treat cancers, including triple-negative breast cancer, by taking advantage of a weakness in cells that was not previously targeted by existing drugs.

The research, which was conducted using isolated cells, human cancer tissue and mouse-grown human cancers, was recently published in nature cancer.

Co-corresponding author of the study and associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics at the University of Texas at Dallas, Dr. Jung-Mo Ahn has devoted more than ten years of his career to the development of small molecules that target protein-protein interactions in cells. He has previously created potential therapeutic candidate compounds for treatment-resistant prostate cancer and breast cancer using a method called structure-based rational drug design.

Jung Mo Ahn

Dr. Jung-Mo Ahn, an associate professor of chemistry and biochemistry at the University of Texas at Dallas, has synthesized a new compound called ERX-41 that kills a wide range of hard-to-treat cancers, including triple breast cancer. negative, by exploiting a weakness in cells that were not previously targeted by other drugs. Credit: University of Texas at Dallas

In current work, Ahn and his colleagues tested a new compound he synthesized called ERX-41 for its effects against breast cancer cells, both those that contain estrogen receptors (ERs) and those that do not contain it. Although there are effective treatments for patients with ER-positive breast cancer, there are few treatment options for patients with triple-negative breast cancer (TNBC), which does not have receptors for estrogen, progesterone, and human epidermal growth factor 2. TNBC typically affects women under 40 and has poorer outcomes than other types of breast cancer.

“The ERX-41 compound didn’t kill healthy cells, but it killed tumor cells, whether or not the cancer cells had estrogen receptors,” Ahn said. “It actually killed triple-negative breast cancer cells better than ER-positive cells.

“It baffled us at the time. We knew it had to target something other than estrogen receptors in TNBC cells, but we didn’t know what it was.

To study the ERX-41 molecule, Ahn worked with collaborators including co-corresponding authors Dr. Ganesh Raj, professor of urology and pharmacology at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center, as well as Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD researcher at Ahn’s Bio-Organic/Medicinal Chemistry Laboratory, was involved in synthesizing the compound.

Researchers found that ERX-41 binds to a cellular protein called lysosomal acid lipase A (LIPA). LIPA is found in a cellular structure called the endoplasmic reticulum, an organelle that processes and folds proteins.

“For a tumor cell to grow quickly, it has to produce a lot of protein, which puts stress on the endoplasmic reticulum,” Ahn said. “Cancer cells significantly overproduce LIPA, much more than healthy cells. By binding to LIPA, ERX-41 blocks protein processing in the endoplasmic reticulum, which becomes swollen, leading to cell death.

The research team also tested the compound on healthy mice and found no adverse effects.

“It took us several years to research exactly which protein was affected by ERX-41. It was the hardest part. We chased a lot of dead ends, but we didn’t give up,” Ahn said.

“Triple negative breast cancer is particularly insidious – it targets women at a younger age; it is aggressive and it is resistant to treatments. I am really happy that we have discovered something that has the potential to make a significant difference for these patients.

The researchers gave the compound to mice with human forms of cancerous tumors, and the tumors grew smaller. The molecule has also been shown to be effective in killing cancer cells in human tissue taken from patients whose tumors had been removed.

They also found that ERX-41 is effective against other types of cancer with high endoplasmic reticulum stress, including difficult-to-treat pancreatic and ovarian cancers and glioblastoma, the most common primary brain cancer. aggressive and deadliest.

“As a chemist, I’m somewhat isolated from patients, so this success is an opportunity for me to feel like what I’m doing can be useful to society,” Ahn said.

Reference: “Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via the induction of endoplasmic reticulum stress” by Xihui Liu, Suryavathi Viswanadhapalli, Shourya Kumar, Tae-Kyung Lee, Andrew Moore, Shihong Ma, Liping Chen, Michael Hsieh, Mengxing Li, Gangadhara R. Sareddy, Karla Parra, Eliot B. Blatt, Tanner C. Reese, Yuting Zhao, Annabel Chang, Hui Yan, Zhenming Xu, Uday P. Pratap, Zexuan Liu, Carlos M. Roggero , Zhenqiu Tan, Susan T. Weintraub, Yan Peng, Rajeshwar R. Tekmal, Carlos L. Arteaga, Jennifer Lippincott-Schwartz, Ratna K. Vadlamudi, Jung-Mo Ahn and Ganesh V. Raj, June 2, 2022, nature cancer.
DOI: 10.1038/s43018-022-00389-8

Ahn is co-holder of issued and pending patents on ERX-41 and related compounds, which have been licensed to Dallas-based startup EtiraRX, a company co-founded in 2018 by Ahn, Raj and Vadlamudi. The company recently announced that it plans to begin clinical trials of ERX-41 as early as the first quarter of 2023.

The study was funded by the National Cancer Institute, the Cancer Prevention and Research Institute of Texas and the Welch Foundation.

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