Featured Research

from universities, journals, and other organizations

Method For Clamping Down On A Cancer-promoting Enzyme Discovered

Date:
April 25, 2008
Source:
Fox Chase Cancer Center
Summary:
Taking a cue from the Croc Hunter, researchers have now identified a molecule capable of taping shut the "jaws" of PAK1 before the enzyme becomes active. The molecule, IPA-3, was shown to be highly specific for PAK1 inhibition in cell cultures studies. Previously, PAK1 activity has been linked with breast cancer and to pathways related to the ras oncogene, which is thought to cause up to 30 percent of all cancers.

There are many pathways that allow an errant gene to turn a cell cancerous, and a number of these pathways go through a single enzyme called the p21-activated kinase 1, or PAK1.

Related Articles


Researchers at Fox Chase Cancer Center have now identified a molecule capable of shutting down PAK1 before the enzyme becomes active. Previous studies have linked PAK1 activity with breast cancer and have shown the enzyme is important in pathways involving the ras oncogene, which is thought to cause up to 30 percent of all cancers.

In the April 24 issue of the journal Chemistry & Biology, the researchers detail how the molecule, called IPA-3, was found from a screen of nearly 33,000 small molecules, and could serve as a basis for future breast cancer or cancer therapeutics. Cell-based studies using IPA-3 confirm that the molecule is capable of blocking signaling by the PAK1 pathway.

"Previous work suggested that hyperactive signaling by PAK1 can contribute to the growth of tumors, but the trick is how to selectively block PAK1 without damaging similar enzymes that are crucial for healthy cellular function," said lead investigator Jeffrey R. Peterson, Ph.D, an associate member of Fox Chase. "IPA-3 represents a proof-of-principle, illustrating a new and highly selective approach to targeting PAK1."

PAK1, like all kinases, is an enzyme that regulates other proteins by attaching an energetic molecule to them in a process known as phosphorylation. The "active site" where the phosphorylation reaction occurs is an attractive target for drug development, since blocking the active site would deactivate the enzyme. Unfortunately, the active site of PAK1 shares a molecular architecture similar to that found in many other kinase enzymes. Previous attempts to inhibit the PAK1 active site chemically have also resulted in inhibiting PAK1-related enzymes, with toxic consequences.

Instead of finding another molecule that binds to the active site, Peterson and his Fox Chase colleagues looked for new molecules that inactivate PAK1 in other ways. The cancer drug Gleevec, for example, is unusually selective for its target by binding to a region outside of the active site that is less common among kinases.

"Many other kinases, including PAK1, have unique regions outside the active site that mediate important facets of their function such as localization, substrate recruitment, or regulation," Peterson says. "We wondered whether these regions might offer other places for molecules to bind and inhibit PAK1 without affecting other enzymes."

According to Peterson, IPA-3 achieves high selectivity for PAK1 by taking advantage of a unique self-regulating region of the enzyme. The PAK1 protein has an auto-regulatory arm, a structure that PAK1 folds over its own active site when the enzyme is not in use. Their findings suggest that IPA-3 binds to the protein when it is in the closed configuration, which then prevents PAK1 from becoming active.

"It is like when the Steve Irwin would subdue a crocodile, he would tape its jaws closed to keep it from biting," Peterson says. "Likewise, IPA-3 latches onto PAK1 in a way that prevents PAK1 from exposing its active site."

Peterson and his colleagues, found IPA-3 by screening a library of over 33,000 small molecules for their ability to block phosphorylation by pure PAK1 protein. Any small molecules that blocked PAK1 were noted and were then ranked by potency, reproducibility and commercial availability. IPA-3 came out ahead of the others through this winnowing process, and the researchers then tested IPA-3 to demonstrate that it could also inhibit PAK1 activity inside living cells.

The Fox Chase researchers believe that IPA-3 represents a promising new strategy for creating therapeutics that inhibit PAK1 by mimicking the way cellular enzymes self-regulate in real life, but the IPA-3 molecule itself is not suitable as a therapeutic in its current form. "IPA-3 requires further experimental study and refinement before it could become a working drug for humans," Peterson says.

The study was funded by grants from the National Institutes of Health, the Department of Defense Neurofibromatosis Research Program, an AACR-Fox Chase Cancer Center Career Development Award in Translational Cancer Research, the National Cancer Institute and the Commonwealth of Pennsylvania.


Story Source:

The above story is based on materials provided by Fox Chase Cancer Center. Note: Materials may be edited for content and length.


Cite This Page:

Fox Chase Cancer Center. "Method For Clamping Down On A Cancer-promoting Enzyme Discovered." ScienceDaily. ScienceDaily, 25 April 2008. <www.sciencedaily.com/releases/2008/04/080418130206.htm>.
Fox Chase Cancer Center. (2008, April 25). Method For Clamping Down On A Cancer-promoting Enzyme Discovered. ScienceDaily. Retrieved March 27, 2015 from www.sciencedaily.com/releases/2008/04/080418130206.htm
Fox Chase Cancer Center. "Method For Clamping Down On A Cancer-promoting Enzyme Discovered." ScienceDaily. www.sciencedaily.com/releases/2008/04/080418130206.htm (accessed March 27, 2015).

Share This


More From ScienceDaily



More Health & Medicine News

Friday, March 27, 2015

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

House Ready to Pass Medicare Doc Bill

House Ready to Pass Medicare Doc Bill

AP (Mar. 26, 2015) In rare bipartisan harmony, congressional leaders pushed a $214 billion bill permanently blocking physician Medicare cuts toward House passage Thursday, moving lawmakers closer to resolving a problem that has plagued them for years. (March 26) Video provided by AP
Powered by NewsLook.com
HIV Outbreak Prompts Public Health Emergency In Indiana

HIV Outbreak Prompts Public Health Emergency In Indiana

Newsy (Mar. 26, 2015) Indiana Gov. Mike Pence says he will bring additional state resources to help stop the epidemic. Video provided by Newsy
Powered by NewsLook.com
Indiana Permits Needle Exchange as HIV Cases Skyrocket

Indiana Permits Needle Exchange as HIV Cases Skyrocket

Reuters - US Online Video (Mar. 26, 2015) Governor Mike Pence declares the recent HIV outbreak in rural Indiana a "public health emergency" and authorizes a short-term needle-exchange program. Rough Cut (no reporter narration) Video provided by Reuters
Powered by NewsLook.com
AAA: Distracted Driving a Serious Teen Problem

AAA: Distracted Driving a Serious Teen Problem

AP (Mar. 25, 2015) While distracted driving is not a new problem for teens, new research from the AAA Foundation for Traffic Safety says it&apos;s much more serious than previously thought. (March 25) Video provided by AP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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