Drug-Like Molecules Indicate New Strategies for Cancer Cells Therapy

Drug-like molecules hold great promise for developing new strategies in cancer cell therapy. These molecules can specifically target cancer cells and disrupt their growth and proliferation, while sparing normal cells.

Ten years ago, genome sequencing unveiled a considerable surprise: almost 50 percent of human cancers are related to mutations known as epigenetic regulators that govern the genes’ activity.

In a recent research in Cell Chemical Biology, a team of scientists directed by Oliver Bell from USC as well as Stephen V. Frye from the University of North Carolina University at Chapel Hill generated a new drug-like molecule that can act against the impacts of mutated epigenetic regulators, which lead to some cancer including lymphoma.

The process by which epigenetic regulators control gene activity.

Epigenetic regulators are essential in healthy cells: triggering the on-and-off action of hundreds of genes in the precisely harmonized sequence which conducts regular human development.

One of these epigenetic regulators, EZH2, regulates the transient inactivation of particular genes, allowing immune cell development. Anyhow, mutated EXH2 can lead to continuous repression of these genes, keeping the immune cells from maturing normally and making them become cancerous malignancies.

The good news is that cancer-causing mutations in epigenetic regulators, different from many other mutations, are more likely to be reversed by therapeutic drugs. Knowing this, first author Junghyun L. Suh and the research team began to create a drug-like molecule to reverse the cancer-causing gene repression by EZH2.

The function of “writers” and “readers.”

Suh and her colleagues began to consider the execution by which EZH2 regulates gene repression. EZH2 functions as a “writer” that indicates which genes will be repressed. CBX8, a second epigenetic regulator, functions as a “reader” that reads these repressive points and engages more regulatory machinery that switches off genes.

In comparison with the writer, the reader CBX8 appears to be evenly critical for the spreading of cancer cells, but it is way more unnecessary for the function of healthy cells. Meanwhile, the drugs that target the reader would be more likely to have less toxic side effects on the healthy cells in the entire patient’s body.

To mainly aim for CBX8, the researchers first designed mouse stem cells by which they could definitely conceal numerous drug-like molecules. These designed stem cells depended on CBX8 reading the marks left by EZH2 to restrain a gene developing a noticeable green fluorescent protein (GFP). The scientists would be sure that a drug-like molecule had undoubtedly blocked CBX8 from interpreting the repressive marks if the stem cells displayed activation of the telltale green light.

Aiming for the “reader” to neutralize the mutation

The researchers afterward speculated their knowledge of CBX8 into many repetitions of drug-like molecules aimed at that specific reader. They considered CBX’s tangled protein structure, also how it links to DNA and reads repressive marks. When they had thrived in synthesizing a strong molecule that performed well in the engineered mouse cells, they proceeded on to testing in human cancer cells.

“The study’s co-corresponding author Oliver Bell, who is an assistant professor of biochemistry and molecular medicine, and stem cell biology and regenerative medicine at the Keck School of Medicine of USC, and an affiliate of the USC Norris Comprehensive Cancer Center, stated that they found that when they exposed human lymphoma and colorectal cancer cells to their newly synthesized drug-like molecule in the laboratory, the cancerous cells stopped Multiplying and began to behave more like healthy cells“.

“The co-corresponding author Stephen V. Frye, who is the Fred Eshelman Distinguished Professor and Co-director of the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill, went on saying that their CBX8-targeted molecule is the most powerful blocker of the reader’s function that they have observed so far. He continued by saying that this opens the door to exploring related cancer therapies and understanding epigenetic regulation in normal human development“.

Read the original article on Sciencedaily.com.

Junghyun L. Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M. Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M. Rectenwald, Jacqueline L. Norris, Stephanie H. Cholensky, Cari Sagum, Jessica D. Umana, Dongxu Li, Brian Hardy, Mark T. Bedford, Shannon M. Mumenthaler, Heinz-Josef Lenz, Yong-Mi Kim, Gang Greg Wang, Ken H. Pearce, Lindsey I. James, Dmitri B. Kireev, Catherine A. Musselman, Stephen V. Frye, Oliver Bell. Reprogramming CBX8-PRC1 function with a positive allosteric modulator. Cell Chemical Biology, 2021; DOI: 10.1016/j.chembiol.2021.10.003

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