Navigation Links
Newly Discovered Compound Blocks Known Cancer-Causing Protein

Duke Comprehensive Cancer Center scientists have discovered a potential new drug that inhibits destructive cell signals that drive the growth of one-third of all cancers. The scientists showed they could block the growth of cultured colon cancer cells using this new compound, called cysmethynil.

Their finding, reported in the March 22, 2005, issue of Proceedings of the National Academy of Sciences, is the first step toward developing a new class of anti-cancer drugs that block the Icmt protein from activating uncontrolled cell growth, a hallmark of cancer, according to Patrick Casey, Ph.D. Casey is the study's senior investigator and Duke pharmacologist and cancer biologist.

Moreover, said Casey, their discovery is the first to emerge from the Duke Small Molecule Screening Facility, which houses a library of more than 13,000 compounds available for screening promising drugs with potential to fight cancer and other diseases. Using automated robotics, the facility provides the kind of drug discovery capability usually available only to pharmaceutical company scientists.

Duke's new facility is a finalist for one of six $9 million National Institutes of Health (NIH) grants that will create a national network of publicly accessible small molecule facilities and make them available to researchers nationwide.

Duke University has filed a patent application for cysmethynil, Casey said, and intends to shepherd it through the first steps of drug development by testing the compound in animal models of cancer.

The research was supported by grant from the NIH and a Howard Hughes Medical Institute predoctoral fellowship to Casey graduate student Ann M. Winter-Vann, the first author of the study.

"This is the first selective small molecule inhibitor of Icmt, a protein that has been shown to be an important player in keeping a cancer-causing gene called 'Ras' turned on inside cells," said Casey.

Ras is a normal genetic component of the cell, but mutations in the gene can cause it to become stuck in an "on" position, promoting uncontrolled cell growth. Mutations in Ras that permanently activate it have been found in half of all colon cancer and 90 percent of pancreatic cancers, among other cancers.

Casey and his colleagues in Duke's Department of Pharmacology and Cancer Biology have already discovered and developed another class of cancer drugs aimed at inhibiting the processing pathway --the prenylation pathway ?that regulates Ras.

Several years ago, Casey's laboratory was one of a handful to unravel how the prenylation pathway works. This accomplishment led pharmaceutical companies to test compounds that block another key player in the pathway, a protein called farnesyltransferase. Blocking this protein inhibits Ras' ability to send growth-promoting signals inside cells. Several such compounds have shown promise in treating leukemias and lymphomas and are now under consideration for final approval by the U.S. Food and Drug Administration.

Since that time, Casey and his colleagues have been studying another key player in the pathway, the Icmt enzyme. Icmt adds a chemical tag called a "methyl group" to Ras. This methyl tag enables Ras to be directed to its final destination in the cell, from where it can send signals for unchecked growth.

"Ras needs to be at the plasma membrane in order to function," he said. "By preventing Icmt from adding a methyl group, we can effectively shut down Ras' ability to function, stopping it from sending signals for uncontrolled growth."

Initial experiments showed that knocking out the Icmt protein using genetic targeting also inhibited Ras, so the scientists decided to search for an effective and specific molecule that could inhibit Icmt function.

"We were looking for a small molecule that inhibited this enzyme specifically, without interfering with the normal regulation of the cell," said Casey. "What we found was a series of 30 structurally related molecules, and we selected the one with the highest potency ?that is cysmethynil."

Once the scientists had identified cysmethynil, they worked with Duke chemist Eric Toone and chemistry graduate student David Gooden to synthesize the molecule and verify its chemical structure. A search of the chemical literature turned up no previous description of the chemical, leading the scientists to believe they had discovered a new chemical compound with a unique biological function.

When the scientists tested the compound's ability to inhibit Ras function in living cells, they found it blocked the ability of colon cancer cells to grow independently in soft agar, a typical test of the cancerous
potential of cells.

"The next step is to test cysmethynil in animal models," said Casey. "We don't know how the compound will be metabolized in living animals, but we are encouraged by our initial results."

Other Duke scientists contributing to the research are Rudi A. Baron, Waihay Wong, June dela Cruz, and John D. York.


'"/>

Source:DukeMedNews


Related biology news :

1. Newly-discovered class of genes determines ?and restricts ?stem cell fate
2. Newly discovered virus linked to childhood lung disorders and Kawasaki disease
3. Newly discovered pathway might help in design of cancer drugs
4. Newly Discovered Branding Process Helps Immune System Cells Pick Their Fights
5. Newly discovered protein an important tool for sleeping sickness research
6. Newly discovered genetic disease sheds light on bodys water balance
7. Newly Discovered Role for Heart Response Enzyme May Yield Better Heart Failure Therapy
8. Newly recognized gene mutation may reduce seeds, resurrect plants
9. Newly discovered birdlike dinosaur is oldest raptor ever found in South America
10. Fitting in: Newly evolved genes adopt a variety of strategies to remain in the gene pool
11. Newly identified mechanism helps explain why people of African descent are more vulnerable to TB
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:6/1/2016)... NEW YORK , June 1, 2016 ... Biometric Technology in Election Administration and Criminal Identification to ... According to a recently released TechSci Research report, " ... Sector, By Region, Competition Forecast and Opportunities, 2011 - ... $ 24.8 billion by 2021, on account of growing ...
(Date:5/12/2016)... DALLAS , May 12, 2016 ... has just published the overview results from the Q1 ... of the recent wave was consumers, receptivity to a ... wearables data with a health insurance company. ... choose to share," says Michael LaColla , CEO ...
(Date:4/28/2016)... -- First quarter 2016:   , Revenues ... first quarter of 2015 The gross margin was 49% ... and the operating margin was 40% (-13) Earnings per ... from operations was SEK 249.9 M (21.2) , Outlook ... 7,000-8,500 M. The operating margin for 2016 is estimated ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... WA (PRWEB) , ... June 23, 2016 , ... ... announces the release of its second eBook, “Clinical Trials Patient Recruitment and Retention ... recruitment and retention in this eBook by providing practical tips, tools, and strategies ...
(Date:6/23/2016)... Mass. , June 23, 2016   ... development of novel compounds designed to target cancer ... napabucasin, has been granted Orphan Drug Designation from ... the treatment of gastric cancer, including gastroesophageal junction ... stemness inhibitor designed to inhibit cancer stemness pathways ...
(Date:6/23/2016)... SILVER SPRING, Md. , June 23, 2016 ... evidence collected from the crime scene to track the criminal ... sick, and the U.S. Food and Drug Administration (FDA) uses ... Sound far-fetched? It,s not. ... whole genome sequencing to support investigations of foodborne illnesses. Put ...
(Date:6/23/2016)... Lawrence, MA (PRWEB) , ... June 23, 2016 ... ... the Peel Plate® YM (Yeast and Mold) microbial test has received AOAC Research ... test platform of microbial tests introduced last year,” stated Bob Salter, Vice President ...
Breaking Biology Technology: