Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Strategy Directly Activates Cellular ‘Death Protein’

04.06.2012
Researchers at Dana-Farber/Children’s Hospital Cancer Center have devised a strategy to directly activate a natural “death” protein, triggering the self-destruction of cells. They say the development could represent a new paradigm for designing cancer drugs.

In an article published as an advanced online publication by Nature Chemical Biology, scientists led by Loren Walensky, MD, PhD, report they identified a prototype compound that “flips a switch” to directly activate one of the most powerful death proteins, known as BAX, triggering apoptosis, or self-destruction of unwanted cells.

“Having identified the ‘on switch’ for the BAX protein several years ago, we now have a small molecule that can directly turn this death protein on,” says Walensky, senior author of the report. The first author, Evripidis Gavathiotis, PhD, carried out the work in Walensky’s laboratory; currently he is an assistant professor at Albert Einstein College of Medicine in New York.

The development exploited the discovery by Walensky’s team of a distinctive groove, or “trigger site,” on the BAX protein that converts it from a quiescent form to an active one. When activated, BAX damages the cell’s mitochondria, releasing signals that break the cell apart and digest its pieces. This process of programmed cell death is part of a natural check-and-balance mechanism to control cellular life and death.

In search of molecular compounds that could fit snugly into the trigger site and jump-start BAX, the investigators used computer-based screening to sift through 750,000 small molecules from commercially available libraries.

The search paid off with the identification of a small-molecule compound named BAM7 (BAX Activator Molecule 7), which selectively bound to BAX and flipped its “on switch,” turning it into an active death protein.

“A small molecule has never been identified before to directly activate BAX and induce cell death in precisely this way,” explains Gavathiotis. “Because BAX is a critical control point for regulating cell death, being able to target it selectively opens the door to a new therapeutic strategy for cancer and perhaps other diseases of cellular excess.”

But wouldn’t switching on cell-death proteins in a patient kill normal cells as well? The researchers say that other compounds now in clinical trials that target the apoptosis pathway haven’t shown such side effects. Gavathiotis suggests that there are sufficient extra survival proteins in normal cells to protect them against pro-death BAX. Cancer cells, however, are under stress and their survival mechanism is stretched to the limit, so that an attack by BAX pushes the cells over the brink into self-destruction.

The Walensky group has previously developed other compounds designed to spur apoptosis of cancer cells. These agents do so either by blocking “anti-death” proteins, deployed by cancer cells to prevent BAX and other death molecules from carrying out their assignment, or by blocking both “anti-death” proteins and activating “pro-death proteins” simultaneously. BAM7 is the first compound that avoids combat with cancer cell’s survival proteins and binds directly and selectively to BAX to turn on cell death.

“We find that small molecule targeting of the BAX trigger site is achievable and could lead to a new generation of apoptotic modulators that directly activate BCL-2 executioner proteins in cancer and other diseases driven by pathologic apoptotic blockades,” write the authors.

Walensky and his colleagues continue to work on BAM7, which is a prototype of drugs that might one day be approved for cancer treatment. Several biotechnology companies have already expressed interest in developing the compound, he says.

Other authors from Walensky’s Dana-Farber lab are Denis Reyna, Joseph Bellairs, and Elizaveta Leshchiner.

The research was funded by the William Lawrence and Blanche Hughes Foundation, with additional support provided by grants from the National Institutes of Health (grants 4R00HL095929 and 5R01CA050239) and Stand Up To Cancer.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

| Newswise Science News
Further information:
http://www.dana-farber.org

Further reports about: BAM7 Cancer Dana-Farber cell death death protein normal cells proteins

More articles from Life Sciences:

nachricht Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care

nachricht Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

NASA detects solar flare pulses at Sun and Earth

17.11.2017 | Physics and Astronomy

NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures

17.11.2017 | Health and Medicine

The importance of biodiversity in forests could increase due to climate change

17.11.2017 | Studies and Analyses

VideoLinks
B2B-VideoLinks
More VideoLinks >>>