|
 Inspired by a rare compound found in a shrub
native to North America, Mingji Dai, professor of chemistry and a
scientist at the Purdue University Center for Cancer Research,
studied the compound and discovered a cost-effective and efficient
way to synthesize it in the lab. The compound — curcusone D — has
the potential to help combat a protein found in many cancers,
including some forms of breast, brain, colorectal, prostate, lung
and liver cancers, among others. The protein, dubbed BRAT1, had
previously been deemed “undruggable” for its chemical properties. In
collaboration with Alexander Adibekian’s group at the Scripps
Research Institute, they linked curcusone D to BRAT1 and validated
curcusone D as the first BRAT1 inhibitor.
Curcusones are compounds that come from a shrub named Jatropha
curcas, also called the purging nut. Native to the Americas, it has
spread to other continents, including Africa and Asia. The plant has
long been used for medicinal properties — including the treatment of
cancer — as well as being a proposed inexpensive source of
biodiesel.
Dai was interested in this family of compounds — curcusone A, B, C
and D.
“We were very interested by these compounds’ novel structure,” Dai
said. “We were intrigued by their biological function; they showed
quite potent anti-cancer activity and may lead to new mechanisms to
combat cancer.”
Researchers tested the compounds on breast cancer cells and found
curcusone D to be extremely effective at shutting down cancer cells.
The protein they were targeting, BRAT1, regulates DNA damage
response and DNA repair in cancer cells. Cancer cells grow very fast
and make a lot of DNA. If scientists can damage cancer cells’ DNA
and keep them from repairing it, they can stop cancer cells from
growing.
dai-m
Mingji Dai, professor of organic chemistry at Purdue University.
(Purdue University photo/Charles Jischke) Download image
“Our compound can not only kill these cancer cells, it can stop
their migration,” Dai said. “If we can keep the cancer from
metastasizing, the patient can live longer.”
Stopping cancer from spreading throughout the body — metastasizing —
is key to preserving a cancer patient’s life. Once cancer starts to
migrate from its original organ into different body systems, new
symptoms start to develop, often threatening the patient’s life.
“For killing cancer cells and stopping migration, there are other
compounds that do that,” Dai said. “But as far as inhibiting the
BRAT1 protein, there are no other compounds that can do that.”
Dai and his team believe that as effective as curcusone D is by
itself, it may be even more potent as part of a combination therapy.
They tested it alongside a DNA damaging agent that has already been
approved by the Food and Drug Administration and found that this
combination therapy is much more effective.
One difficulty in studying curcusones as potential cancer treatments
is that, while the shrub they come from is common and inexpensive,
it takes massive amounts of the shrub to yield even a small amount
of the compounds. Even then, it is difficult to separate the
compounds they were interested in from the rest of the chemicals in
the shrub’s roots. “In nature, the plant
doesn’t produce a lot of this compound,” Dai said. “You would need
maybe as much as 100 pounds of the plant’s dry roots to get just
about a quarter teaspoon of the substance — a 0.002% yield.”
[to top of second column] |
That small yield is relevant for production, because
if it is effective as a cancer treatment, pharmacists will need a
lot more of it. Additionally, having an abundant supply of the
compounds makes studying them easier, quicker and less expensive.
“That’s why a new synthesis is so important,” Dai said. “We can use
the synthesis to produce more compounds in a purer form for
biological study, allowing us to advance the field. From there, we
can make analogs of the compound to improve its potency and decrease
the potential for side effects.”
The next step will be to test the compound to ensure that it is not
toxic to humans, something the researchers are optimistic about
since the shrub it came from has been used as a traditional medicine
in a number of cultures. Already, researchers from other entities
have reached out to test the compound on the cancers they study,
bringing hope for renewed therapeutics for treating the disease.
“Many of our most successful cancer drugs have come from nature,”
Dai said. “A lot of the low-hanging fruit, the compounds that are
easy to isolate or synthesize, have already been screened and picked
over. We are looking for things no one has thought about before.
Once we have the chemistry, we can build the molecules we’re
interested in and study their biological function.”
This research was funded through grants from the National Institutes
of Health and the National Science Foundation. Patent application
U.S. 63/084,594 covers this finding.
About Purdue University Center for Cancer Research
At the Purdue University Center for Cancer Research, our mission is
basic discovery — discovery that is the foundation for innovative
cancer solutions. PCCR leverages Purdue's strengths in engineering,
veterinary medicine, nutrition science, chemistry, medicinal
chemistry, pharmacy, structural biology and biological sciences to
establish its foundational base. As a National Cancer
Institute-designated cancer center, PCCR is making significant
contributions to emerging technologies, such as cancer vaccines and
combination chemotherapy. We specialize in translational research
that saves lives by translating laboratory findings into new and
innovative therapies as quickly as possible. Our mission is
discovery. Our goal is to cure cancer.
About Purdue University
Purdue University is a top public research institution developing
practical solutions to today’s toughest challenges. Ranked the No. 5
Most Innovative University in the United States by U.S. News & World
Report, Purdue delivers world-changing research and
out-of-this-world discovery. Committed to hands-on and online,
real-world learning, Purdue offers a transformative education to
all. Committed to affordability and accessibility, Purdue has frozen
tuition and most fees at 2012-13 levels, enabling more students than
ever to graduate debt-free. See how Purdue never stops in the
persistent pursuit of the next giant leap at https://purdue.edu/.
[Writer: Brittany
Source: Mingji Dai] |
