Novel PROTAC enhances its intracellular accumulation and protein
knockdown

Date:
August 26, 2020
Source:
Baylor College of Medicine
Summary:
Researchers have developed an improved type of PROTAC that has
enhanced intracellular accumulation and functions, not only as a
degrader, but also as an inhibitor of the target protein.



FULL STORY ========================================================================== Cancer therapies sometimes involve drugs that mediate the breakdown of
specific intracellular proteins that participate in cancer formation
and proliferation.

Proteolysis-targeting chimeras or PROTACs are a promising type of protein- degrader molecules, but their effectiveness has been challenged by their limited ability to accumulate inside cells.


==========================================================================
In this study published in the journal Nature Communications, a team led
by researchers at Baylor College of Medicine developed an improved type
of PROTAC that has enhanced intracellular accumulation and functions, not
only as a degrader, but also as an inhibitor of the target protein. This exciting discovery led to a recently funded research grant from the
National Cancer Institute (NCI) scored at top one percentile. The
researchers hope that their work can be used to develop optimal PROTACs
for clinical applications in the future.

"PROTACs are molecules made of two parts: one binds to the target protein
and the other links to the enzyme ubiquitin ligase. The two parts are
joined by a chemical linker," said corresponding author Dr. Jin Wang,
associate professor of pharmacology and chemical biology and of molecular
and cellular biology at Baylor.

Once PROTAC binds to its target protein and the ubiquitin ligase, the
ligase will attach ubiquitin groups to the surface of the target protein,
which tags it for degradation by the proteasome inside the cell.

Wang and his colleagues were interested in improving PROTAC's ability
to degrade target proteins inside cells. Drawing from their years of
expertise in the fields of organic chemistry and chemical biology,
they experimented with different chemical binders to determine how they affected PROTAC's efficacy.

Serendipitously, they discovered that a specific type of chemistry can
enhance PROTAC's intracellular accumulation.

Making an improved PROTAC The researchers worked with a well-known
target of PROTAC, the enzyme Bruton's tyrosine kinase (BTK). They used different types of binders -- reversible noncovalent, reversible covalent,
and irreversible covalent -- to construct PROTACs that targeted BTK.

"When we compared the different constructs in their ability to degrade
BTK, we were excited to discover that the cyano-acrylamide-based
reversible covalent chemical binder significantly enhanced the
intracellular accumulation and target engagement of PROTACs, much better
than the others," said co-first author Dr. Wen-Hao Guo, a postdoctoral associate in the Wang lab.

"Furthermore, we developed RC-1, a reversible covalent BTK PROTAC that was effective as both a BTK inhibitor and degrader," said co-first author Dr.

Xiaoli Qi, assistant professor in pharmacology and chemical biology
at Baylor.

"This represents a novel mechanism of action for PROTACs. Our work
suggests the possibility that this strategy to improve PROTACs can be
applied to target other molecules."

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Wen-Hao Guo, Xiaoli Qi, Xin Yu, Yang Liu, Chan-I Chung, Fang Bai,
Xingcheng Lin, Dong Lu, Lingfei Wang, Jianwei Chen, Lynn Hsiao
Su, Krystle J. Nomie, Feng Li, Meng C. Wang, Xiaokun Shu, Jose'
N. Onuchic, Jennifer A. Woyach, Michael L. Wang, Jin Wang. Enhancing
intracellular accumulation and target engagement of PROTACs with
reversible covalent chemistry. Nature Communications, 2020; 11
(1) DOI: 10.1038/s41467-020- 17997-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200826123123.htm

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