Scientists have discovered a new molecule that can kill even the most dangerous cancer

Recently, a small group of people with rectal cancer saw that the disease had disappeared after experimental treatment.

It was a very small test performed by doctors at the Memorial Sloan Kettering Cancer Center in New York City, where patients took a drug called dosarlimab for six months. By the end of the trial, each tumor had disappeared.

Now, in another revelation, Dr. Jung-Moo An, a researcher at the University of Texas at Dallas, found that it killed a wide range of difficult-to-treat cancers, including triple-negative breast cancer, without damaging healthy cells.

He took advantage of the weakness of cells that had not been targeted by other drugs so far.

A study of isolated cells in both human cancerous tissue and human cancerous growths in mice was published in the journal. Natural Cancer.

Corresponding author and associate professor of chemistry and biochemistry at UT Dallas School of Natural Sciences and Mathematics, Ann has been working on small molecules for more than a decade, targeting protein-cell interactions. He has previously developed compounds that are potential therapeutic candidates for the treatment of resistant breast cancer and prostate cancer.

In a current study, Ann and her colleagues tested a new compound he synthesized called ERX-41, which has effects on breast cancer cells – with and without estrogen receptors (ERs).

Currently, there are effective treatments for patients with ER-positive breast cancer, but there are only a few treatment options for patients with triple-negative breast cancer (TNBC). It lacks receptors for estrogen, progesterone and growth factor 2 in the human epidermis. TNBC affects women under the age of 40 and has worse outcomes than other types of breast cancer.

“The ERX-41 compound did not kill healthy cells, but whether or not the cancer cells had estrogen receptors, it did destroy the tumor cells,” Ann said. “In fact, it killed three times more negative breast cancer cells than it did destroying ER-positive cells.

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

Dr. Jung-Mo An, an associate professor of chemistry and biochemistry at UT Dallas, has synthesized a new compound called ERX-41 that promises to kill cancer cells. Source: UT Dallas

No adverse effects in healthy mice

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

“For a tumor cell to grow rapidly, it must produce a lot of protein, and this puts stress on the endoplasmic reticulum,” Anne said. “Cancer cells produce more LIPA than healthy cells. By binding to LIPA, ERX-41 stops the processing of protein in the endoplasmic reticulum, leading to cell death.”

The team tested the molecule in healthy mice and noted no side effects.
“It took us years to figure out exactly which protein ERX-41 was affecting. It was the hardest part. We’ve gotten through a lot of deadlocks, but we haven’t given up,” Ann said.

“Three-negative breast cancer is particularly subtle – it targets young women; it is aggressive and resistant to treatment. I’m very happy to find something that can make a difference for these patients,” Ah said.

Can overcome the most dangerous cancer

The researchers then gave the compound to mice with human forms of cancer, and they shrunk.

The molecule also kills cancer cells in human tissue collected from patients who have had their tumors removed.

There is more.

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

To study the ERX-41 molecule, Ann collaborated with co-authors, including the authors. Ganesh Raj, Professor of Urology and Pharmacology at Harold Simmons Complex Oncology Center at UT Southwestern Medical Center, as well as Dr. Ratna Wadlamudi, Professor of Obstetrics and Gynecology at UT Health San Antonio. Dr. Tae-Kyung Lee, a former UTD researcher at Andy’s Bio-Organic / Medicinal Chemistry Laboratory, was also involved in the compound synthesis.

He is the co-owner of the ERX-41 and related compounds patents issued in 2018 by Ahn, Raj and Wadlamudi for the EliraRX startup in Dallas. The company has announced that it plans to begin clinical trials of ERX-41 in the first quarter of 2023, which gives hope for an effective new treatment.

Annotation: Triple-negative breast cancer (TNBC) has a poor clinical outcome because of a lack of possible therapeutic targets. Here, we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress leading to cell death, and this effect is targeted. LIPA resistance mutations. Importantly, we show that ERX-41 activity is independent of LIPA lipase function but depends on its ER localization. Mechanically, the ERX-41 LIPA bond reduces the expression of several ER-resident proteins involved in protein folding. This target vulnerability has a large therapeutic window, without adverse effects on normal mammary gland epithelial cells or mice. Our study includes a targeted strategy for solid tumors, including the breast, brain, pancreas, and ovaries, whereby small, orally bioavailable molecules aimed at folding the LIPA protein cause ER stress and lead to tumor cell death.

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