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

Join For Free

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 3,500+ scientific posters on ePosters
  • More Than 5,000+ 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

Disordered Protein 'Shape Shifts' to Avoid Crowding
Study suggests disordered protein escapes from the cell membrane when it runs out of space.
Wednesday, September 21, 2016
Antibodies that Target Holes in HIV's Defence Identified
Scientists suggest 'holes' in HIV sugar sheild can be targeted by antibodies.
Friday, September 16, 2016
'Missing Evolutionary Link' of a Widely Used Natural Drug Source Found
A well-known family of natural compounds, called “terpenoids,” have a curious evolutionary origin. In particular, one question relevant to future drug discovery has puzzled scientists: exactly how does Nature make these molecules?
Tuesday, August 30, 2016
‘Lead Actors’ in Immune Cell Development Uncovered
A new study, led by scientists at The Scripps Research Institute (TSRI), reveals a surprising twist in immune biology.
Tuesday, August 30, 2016
'Missing Evolutionary Link' of Natural Drug Source Found
Scripps Florida study finds 'missing evolutionary link' of a widely used natural drug source
Monday, August 22, 2016
4 Billion-Year-Old RNA Synthesized
TSRI are one step closer to the lab recreation of the "RNA world" of 4 billion years ago.
Wednesday, August 17, 2016
Surprising Twist in Immune Biology
TSRI researchers have found the ‘lead actors’ in immune cell development, shedding light on casues of autoimmune disease.
Wednesday, August 03, 2016
Influencing the Immune System
A TSRI study has opened the door to influencing the immune system, yielding possible boosts to vaccine efficiency and immunology.
Tuesday, August 02, 2016
Drug Candidates Reduce Abnormal Protein Production
New drug candidates improve cell ability to catch miss-folded proteins that could cause deadly diseases.
Friday, July 22, 2016
Scientists Link Bipolar Disorder to Unexpected Brain Region
Researchers from The Scripps Research Institute have found that gene within the brain’s striatum could be linked to biopolar disorder.
Wednesday, July 20, 2016
New Cancer Drug Target Found in Dual-Function Protein
Findings from a study from TSRI have shown that targeting a protein called GlyRS might help to halt cancer growth.
Wednesday, June 29, 2016
HIV Structure Stabilized
Findings represent ‘big accomplishment’ in biomedical engineering and design.
Wednesday, June 29, 2016
New Method Opens Door to Development of Many New Medicines
Findings from TSRI reveal human proteins are better drug targets than previously thought.
Friday, June 17, 2016
Harnessing Nature’s Vast Array of Venoms for Drug Discovery
Scripps scientists have developed a method for rapidly identifying venoms.
Wednesday, May 25, 2016
Breakthrough Approach to Breast Cancer Treatment
Scripps scientists have designed a drug candidate that decreases growth of breast cancer cells.
Tuesday, May 24, 2016
Scientific News
Point of Care Diagnostics - A Cautious Revolution
Advances in molecular biology, coupled with the miniaturization and improved sensitivity of assays and devices in general, have enabled a new wave of point-of-care (POC) or “bedside” diagnostics.
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
Researchers Find a Gap in the Brain’s Firewall Against Parkinson’s Disease
Researchers at NIH have found mouse study that identified a key player in the progression of the disorder.
Fat Cells That Amplify Nerve Signals in Response to Cold Also Affect Blood Sugar Metabolism
Researchers at UTSW have found that the protein connexin 43 forms cell-to-cell communication channels on the surface of emerging beige fat cells that amplify the signals from those few nerve fibers.
Drug to Treat Alcohol Use Disorder Shows Promise Among Drinkers With High Stress
The findings suggest that potential future studies with drugs targeting vasopressin blockade should focus on populations of people with AUD who also report high levels of stress.
C Dots Show Powerful Tumor Killing Effect
Nanoparticles known as Cornell dots, or C dots, have shown great promise as a therapeutic tool in the detection and treatment of cancer.
Faecal Bacteria Linked to Body Fat
Researchers at King’s College London have found a new link between the diversity of bacteria in human poo – known as the human faecal microbiome - and levels of abdominal body fat.
How Baby’s Genes Influence Birth Weight And Later Life Disease
The large-scale study could help to target new ways of preventing and treating these diseases.
Genes Underlying Dogs’ Social Ability Revealed
The social ability of dogs is affected by genes that also seem to influence human behaviour, according to a new study from Linköping University in Sweden.
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
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!