Drug-like molecule points to novel strategies for cancer therapy

Date:
October 29, 2021
Source:
Keck School of Medicine of USC
Summary:
A decade ago, genome sequencing revealed a big surprise: about
50 percent of human cancers are linked to mutations in what are
known as epigenetic regulators, which control the activity of
genes. Medical researchers have now developed a new drug-like
molecule that can counteract the effects of mutated epigenetic
regulators, which are known to drive certain types of cancer
including lymphoma.



FULL STORY ==========================================================================
A decade ago, genome sequencing revealed a big surprise: about 50 percent
of human cancers are linked to mutations in what are known as epigenetic regulators, which control the activity of genes.


==========================================================================
In a new study in Cell Chemical Biology, a team of scientists led by
Oliver Bell from USC and Stephen V. Frye from the University of North
Carolina at Chapel Hill developed a new drug-like molecule that can
counteract the effects of mutated epigenetic regulators, which are known
to drive certain types of cancer including lymphoma.

How epigenetic regulators control gene activity In healthy cells,
epigenetic regulators play an essential role: turning on and off the
activity of hundreds of genes in the precisely orchestrated sequence
that directs normal human development.

One of these epigenetic regulators, EZH2, controls the transient
inactivation of specific? genes in order to permit the maturation of
immune cells. However, mutated EZH2 may cause persistent repression of
these genes, thus preventing the immune cells from developing normally
and ultimately leading them to transform into cancerous malignancies.

The good news is that in contrast to many other types of mutations,
cancer- causing mutations in epigenetic regulators are potentially
reversible by therapeutic drugs. With this in mind, first author Junghyun
L. Suh and the research team set out to design a drug-like molecule to
reverse the cancer- causing gene repression by EZH2.



==========================================================================
The role of "writers" and "readers" Suh and her colleagues started by considering the mechanism by which EZH2 controls gene repression. EZH2
acts as a "writer" that marks which genes will be repressed. A second epigenetic regulator called CBX8 serves as a "reader" that interprets
these repressive marks, and recruits additional regulatory machinery
that actually turns off the genes.

Compared to the writer, the reader CBX8 seems to be equally critical
for the proliferation of cancer cells, but is more dispensable for the
function of healthy cells. This means that drugs targeting the reader
would be expected to have fewer toxic side effects on the healthy cells throughout a patient's body.

To specifically target CBX8, the researchers first engineered mouse
stem cells in which they could easily screen a large number of drug-like molecules. These engineered stem cells relied on CBX8 reading the marks deposited by EZH2 to repress a gene producing a visible green fluorescent protein (GFP). If the stem cells showed activation of the telltale green
glow, the scientists knew that a drug-like molecule had successfully
prevented CBX8 from reading the repressive marks.

Targeting the "reader" to counteract the mutation The researchers then
parlayed their knowledge of CBX8 into several iterations of drug-like
molecules that targeted this particular reader. They took into account
CBX's intricate protein structure, as well as the way that it binds to
DNA and reads repressive marks. When they had succeeded in synthesizing
a potent molecule that worked well in the engineered mouse cells, they
moved on to testing in human cancer cells.

"When we exposed human lymphoma and colorectal cancer cells to our newly synthesized drug-like molecule in the laboratory, the malignant cells
ceased to proliferate and began to behave more like healthy cells," said
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 a
member of the USC Norris Comprehensive Cancer Center.

"Our CBX8-targeted molecule has the most powerful effect that we've seen
so far in terms of blocking the reader's function," added 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. "This opens
a path to exploring related cancer therapies, as well as to enhancing
our understanding of epigenetic regulation in normal human development." ========================================================================== Story Source: Materials provided by
Keck_School_of_Medicine_of_USC. Original written by Cristy Lytal. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211029103124.htm

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