Scientists reengineer cancer drugs to be more versatile
Control of specific gene-expression pathways could spur better treatment
of many diseases

Date:
February 15, 2023
Source:
Rice University
Summary:
Scientists enlist widely used cancer therapy systems to control
gene expression in mammalian cells, a feat of synthetic biology
that could change how diseases are treated.


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FULL STORY ==========================================================================
Rice University scientists have enlisted widely used cancer therapy
systems to control gene expression in mammalian cells, a feat of synthetic biology that could change how diseases are treated.


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The lab of chemical and biomolecular engineer Xue Sherry Gao discovered
a way to further tap the therapeutic potential of proteolysis targeting chimeras (PROTACs), small molecules that are used as effective tools for treating cancer, immune disorders, viral infections and neurodegenerative diseases.

Gao and collaborators reengineered the PROTAC molecular infrastructure and showed it can be used to achieve chemically induced dimerization (CID),
a mechanism by which two proteins bind together only in the presence of
a specific third molecule known as an inducer. The research is described
in a study published in the Journal of the American Chemical Society.

"The novelty of this is the extent of control that combining these two mechanisms gives us over inducing gene activation at desired locations
in the body and for desired durations," Gao said.

"Small molecules can act as a switch to turn gene expression on and off,"
she said. "Temporal control is a result of the fact that small molecules
are metabolized by living organisms. What this means is that you can
schedule for a certain gene to be expressed for a certain amount of time.

"In terms of spatial control, we can deliver the system only to the
organ or site of the body where it is needed," Gao continued. "You don't
need to have the medication go through your whole body and generate
unnecessary and harmful toxicity." The CID mechanism is a key part of
many biological processes, and over the past two decades scientists have devised a host of ways to engineer it to serve medical, research and
even manufacturing needs. The development highlights the growing impact
of synthetic biology, which takes an engineering approach to biological systems, repurposing their mechanisms to harness new resources.

Sirolimus, formerly known as rapamycin. is an example of a molecule that
can act as an inducer and form CID systems with multiple cell pathways
in the body.

Discovered in 1972 in soil bacteria on Easter Island, the compound has
been used as an antitumor and immunosuppressant drug. More recently, it
was touted as a potential anti-aging drug after researchers discovered
it could interfere with a cellular pathway that activates lysosomes,
organelles responsible for cleaning up damaged cells.

"CID systems are attractive tools because they enable precise control over molecular interactions, which in turn can activate or inhibit biological outcomes, such as, for example insulin production in a diabetic patient
or tumor growth in a cancer patient," Gao said.

"Right now there are only a limited number of functional and efficient
CID systems," she added. "I wanted to address this unmet need. I saw
PROTACs, which are already being used with good results as therapies,
as an opportunity to expand the CID toolbox." PROTACs work by targeting specific proteins, such as those found in a tumor, causing them to disintegrate. One side of the molecule binds to a targeted harmful
protein, another side flags down a specific enzyme that initiates protein degradation and a third element connects the two sides together.

"You can think of this mechanism as similar to a smart missile that relies
on a sensor to track its target," Gao said. "The vocabulary is suggestive
in this sense, too, since the protein you want to destroy is called a
'target protein,' and the part of the PROTAC system that binds to the
target protein is called a 'warhead.' We are hijacking this system to
control gene expression instead." The advantage of PROTACs over other
drugs is that they can be effective in small doses and do not lead to
the development of drug resistance. There are over 1,600 PROTAC small
molecules approved for cancer therapy, acting on more than 100 human
protein targets.

"PROTACs are very efficient and act with great specificity against
oncogenic proteins, which are proteins encoded by certain activated or dysregulated genes that have a potential to cause cancer," Gao said. "We
wanted to harness that efficiency and precision and put it to work in
a new way. We redesigned PROTAC from a protein-degradation system to a gene-activation system.

"Ultimately, I hope this will prove useful in the context of treating
real diseases," she continued. "The ability to regulate when and
where genes are activated in the body could help solve a wide range
of medical problems. My main goal with this project is to have a small molecule-controlled gene expression system, including the CRISPR genome editors." Gao is Rice's T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering
and chemistry. The study was developed in collaboration with the Zheng
Sun lab at Baylor College of Medicine.

The National Science Foundation (2143626), the Robert A. Welch
Foundation (C- 1952), the National Institutes of Health (HL157714,
HL153320, DK111436, AG069966, ES027544), the John S. Dunn Foundation,
the Clifford Elder White Graham Endowed Research Fund, the Cardiovascular Research Institute at Baylor College of Medicine, the Dan L. Duncan Comprehensive Cancer Center (P30CA125123), the Specialized Programs of
Research Excellence (P50CA126752), the Gulf Coast Center for Precision Environmental Health (P30ES030285) and the Texas Medical Center Digestive Diseases Center (P30DK056338) supported the research.

* RELATED_TOPICS
o Health_&_Medicine
# Human_Biology # Personalized_Medicine #
Diseases_and_Conditions # Medical_Topics # Lung_Cancer #
Gene_Therapy # Genes # Cancer
* RELATED_TERMS
o Gene_therapy o Bioinformatics o Cancer o Prostate_cancer o
BRCA1 o Stem_cell o Embryonic_stem_cell o Human_biology

========================================================================== Story Source: Materials provided by Rice_University. Original written
by Silvia Cernea Clark.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Dacheng Ma, Qichen Yuan, Fei Peng, Victor Paredes, Hongzhi Zeng,
Emmanuel
C. Osikpa, Qiaochu Yang, Advaith Peddi, Anika Patel, Megan S. Liu,
Zheng Sun, Xue Gao. Engineered PROTAC-CID Systems for Mammalian
Inducible Gene Regulation. Journal of the American Chemical Society,
2023; 145 (3): 1593 DOI: 10.1021/jacs.2c09129 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/02/230215143648.htm

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