Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Chemists Discover Cancer Drug Candidate Structure

Published: Wednesday, May 21, 2014
Last Updated: Wednesday, May 21, 2014
Bookmark and Share
Chemists at The Scripps Research Institute have determined the correct structure of a highly promising anticancer compound approved by the U.S. FDA for clinical trials in cancer patients.

The new report, published this week by the international chemistry journal Angewandte Chemie, focuses on a compound called TIC10.

In the new study, the TSRI scientists show that TIC10’s structure differs subtly from a version published by another group last year, and that the previous structure associated with TIC10 in fact describes a molecule that lacks TIC10’s anticancer activity.

By contrast, the correct structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for their possible therapeutic uses.

“This new structure should generate much interest in the cancer research community,” said Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.

Antitumor Potential
TIC10 was first described in a paper in the journal Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells’ production of a powerful natural antitumor protein, TRAIL. (TIC10 means TRAIL-Inducing Compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper, which drew widespread media coverage, reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice, including notoriously treatment-resistant glioblastomas.

Tumors can develop resistance to TRAIL, but Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention. “I thought, ‘They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor cell TRAIL resistance—the combination could be important,’” he said.

The original publication on TIC10 included a figure showing its predicted structure. “I saw the figure and asked one of my postdocs, Jonathan Lockner, to make some,” Janda said.

Although the other team had seemingly confirmed the predicted structure with a basic technique called mass spectrometry, no one had yet published a thorough characterization of the TIC10 molecule. “There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis,” Lockner said. “My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds.”

Surprising Inactivity
There was just one problem with Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.

“Of course I was nervous,” remembered Lockner. “As a chemist, you never want to make a mistake and give biologists the wrong material.”

To try to verify they had the right material, Janda’s team obtained a sample of TIC10 directly from the NCI. “When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect,” said Nicholas Jacob, a graduate student in the Janda Laboratory who, with Lockner, was a co-lead author of the new paper. “That prompted us to look more closely at the structures of these two compounds.”

The two researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. With Assistant Professor Vladimir V. Kravchenko of the TSRI Department of Immunology and Microbial Science, Jacob also tested the two compounds’ biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The Right Structure
The originally published structure has a core made of three carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle. In chemists’ parlance, the two compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angularimidazolinopyrimidinone.

Ironically, Lockner found that the angular TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer. The angular core of the TRAIL-inducing molecule discovered by Janda’s team turns out to be a novel type of a biologically active structure—or “pharmacophore”—from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

 “One lesson from this has got to be: don’t leave your chemists behind,” said Janda.

Funding for the research, published in a paper titled “Pharmacophore Reassignment for Induction of the Immunosurveillant TRAIL” (DOI: 10.1002/anie.201), was provided by The Skaggs Institute for Chemical Biology and TSRI. 


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More Than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Antibody Weapons Against Marburg Virus
A study has identified new immune molecules that protect against deadly Marburg virus, a relative of Ebola virus.
Tuesday, June 30, 2015
Team Led by TSRI Scientists Shows AIDS Vaccine Candidate Successfully ‘Primes’ Immune System
New research shows that an experimental vaccine candidate can stimulate immune activity necessary to prevent HIV infection.
Thursday, June 25, 2015
New Details of Potential Alzheimer’s Treatment Uncovered
Scientists from Florida’s Scripps Resarch Institute have uncovered suprising new details of potential Alzheimer’s treatment.
Wednesday, April 29, 2015
Search for Cancer Drug Candidates
Scripps Florida scientists awarded $1.2 million to find drug candidates that could treat a wide range of cancers.
Friday, April 10, 2015
Scripps Florida Scientists Win $1.5 Million Grant to Develop New Cancer Drugs
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded a $1.5 million grant from the National Institutes of Health (NIH) to develop drug candidates that could treat cancer and neurodegenerative disease.
Tuesday, March 24, 2015
Day-Night Cycles Linked to Mutations
TSRI scientists show that proteins critical in day-night cycles also protect cells from mutations.
Friday, March 13, 2015
More DNA & Extra Copies of Disease Gene in Alzheimer’s Brain Cells
Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer’s patients, pointing to an unexpected factor that may underpin the most common form of the disease.
Tuesday, February 24, 2015
Possible Neuron Killing Mechanism Behind Alzheimer’s and Parkinson’s Diseases Discovered
$1.4 million grant will enable team to follow up with search for drug candidates.
Tuesday, February 17, 2015
Microbes Prevent Malnutrition in Fruit Flies—and Maybe Humans, Too
Study shows that microbes play a critical role in nutritional disorders.
Friday, February 13, 2015
New Targets and Test to Develop Treatments for Memory Disorders
The study focuses on kinesin, a molecular motor protein that plays a role in the transport of other proteins throughout a cell.
Thursday, November 13, 2014
MS Drug Candidate Shows Promise for Ulcerative Colitis
Positive new clinical data were released today on a drug candidate for ulcerative colitis that was first discovered and synthesized at The Scripps Research Institute.
Thursday, October 30, 2014
New Technique has Profound Implications for Drug Development
The method, developed by Scripps Research Institute chemists, expands options for making pure batches of ‘one-handed’ molecules.
Thursday, October 30, 2014
Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Enzyme Could Help Explain Origins of Life
Mimicking natural evolution in a test tube, scientists at The Scripps Research Institute (TSRI) have devised an enzyme with a unique property that might have been crucial to the origin of life on Earth.
Wednesday, October 29, 2014
Revealing Molecular Secrets Behind the Health Benefits of Wine
Resveratrol has been much in the news as the component of grapes and red wine associated with reducing “bad cholesterol,” heart disease and some types of cancer.
Wednesday, April 30, 2014
Scientific News
RNAi Screening Trends
Understand current trends and learn which application areas are expected to gain in popularity over the next few years.
Diagnostic Test Developed for Enterovirus D68
researchers at Washington University School of Medicine in St. Louis have developed a diagnostic test to quickly detect enterovirus D68 (EV-D68), a respiratory virus that caused unusually severe illness in children last year.
How a Kernel Got Naked and Corn Became King
Ten thousand years ago, a golden grain got naked, brought people together and grew to become one of the top agricultural commodities on the planet.
Sweet Revenge Against Superbugs
A special type of synthetic sugar could be the latest weapon in the fight against superbugs.
New Material Opens Possibilities for Super-Long-Acting Pills
A pH-responsive polymer gel could create swallow able devices, including capsules for ultra-long drug delivery.
How To Keep Your Rice Arsenic-Free
Researchers at Queen’s University Belfast have made a breakthrough in discovering how to lower worrying levels of arsenic in rice that is eaten all over the world.
New Tool For Investigating RNA Gone Awry
A new technology – called “Sticky-flares” – developed by nanomedicine experts at Northwestern University offers the first real-time method to track and observe the dynamics of RNA distribution as it is transported inside living cells.
Computer Model Could Explain how Simple Molecules Took First Step Toward Life
Two Brookhaven researchers developed theoretical model to explain the origins of self-replicating molecules.
New Tech Enables Epigenomic Analysis with a Mere 100 Cells
A new technology that will dramatically enhance investigations of epigenomes, the machinery that turns on and off genes and a very prominent field of study in diseases such as stem cell differentiation, inflammation and cancer has been developed by researchers at Virginia Tech.
Access Denied: Leukemia Thwarted by Cutting Off Link to Environmental Support
A new study reveals a protein’s critical – and previously unknown -- role in the development and progression of acute myeloid leukemia (AML), a fast-growing and extremely difficult-to-treat blood cancer.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!