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 Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>