Featured Research

from universities, journals, and other organizations

New strategy directly activates cellular 'death protein'

Date:
May 31, 2012
Source:
Dana-Farber Cancer Institute
Summary:
Researchers have devised a strategy to directly activate a natural "death" protein, triggering the self-destruction of cells -- which could lead to new possibilities for designing cancer drugs.

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.


Story Source:

The above story is based on materials provided by Dana-Farber Cancer Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Evripidis Gavathiotis, Denis E Reyna, Joseph A Bellairs, Elizaveta S Leshchiner, Loren D Walensky. Direct and selective small-molecule activation of proapoptotic BAX. Nature Chemical Biology, 2012; DOI: 10.1038/nchembio.995

Cite This Page:

Dana-Farber Cancer Institute. "New strategy directly activates cellular 'death protein'." ScienceDaily. ScienceDaily, 31 May 2012. <www.sciencedaily.com/releases/2012/05/120531135743.htm>.
Dana-Farber Cancer Institute. (2012, May 31). New strategy directly activates cellular 'death protein'. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2012/05/120531135743.htm
Dana-Farber Cancer Institute. "New strategy directly activates cellular 'death protein'." ScienceDaily. www.sciencedaily.com/releases/2012/05/120531135743.htm (accessed July 28, 2014).

Share This




More Health & Medicine News

Monday, July 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Trees Could Save More Than 850 Lives Each Year

Trees Could Save More Than 850 Lives Each Year

Newsy (July 27, 2014) A national study conducted by the USDA Forest Service found that trees collectively save more than 850 lives on an annual basis. Video provided by Newsy
Powered by NewsLook.com
Google's Next Frontier: The Human Body

Google's Next Frontier: The Human Body

Newsy (July 27, 2014) Google is collecting genetic and molecular information to paint a picture of the perfectly healthy human. Video provided by Newsy
Powered by NewsLook.com
What's To Blame For Worst Ebola Outbreak In History?

What's To Blame For Worst Ebola Outbreak In History?

Newsy (July 27, 2014) A U.S. doctor has tested positive for the deadly Ebola virus, as the worst-ever outbreak continues to grow. Video provided by Newsy
Powered by NewsLook.com
Losing Sleep Leaves You Vulnerable To 'False Memories'

Losing Sleep Leaves You Vulnerable To 'False Memories'

Newsy (July 27, 2014) A new study shows sleep deprivation can make it harder for people to remember specific details of an event. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins