Corporate Banner
Satellite Banner
Medicinal Chemistry
Scientific Community
Become a Member | Sign in
Home>News>This Article

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 2,800+ scientific posters on ePosters
  • More than 4,000+ 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 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

$6 Million Awarded to Develop Alternative HIV/AIDS Vaccine
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to nearly $6 million from the Bill & Melinda Gates Foundation to develop a revolutionary HIV/AIDS alternative vaccine that has demonstrated great potential in animal models.
Thursday, September 24, 2015
Scientists Make Strides in Therapy Preventing Addiction Relapse
Single Injection of Drug Candidate Prevents Meth Relapse in Animal Models.
Thursday, August 06, 2015
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 Creates New Drug Discovery Initiative
Scripps Advance is a new drug discovery initiative to translate early-stage biomedical research projects into clinical development candidates.
Wednesday, April 16, 2014
New Findings from The Scripps Research Institute Could Help Improve Development of Drugs for Addiction
Scientists have described findings that could enable the development of more effective drugs for addiction with fewer side effects.
Thursday, August 08, 2013
Micah Niphakis Receives ACS Scarborough Award
Niphakis’s research focuses on the development of chemical tools to comprehensively map bioactive molecule-protein interactions in the cell.
Monday, January 21, 2013
Scripps Scientists Reveal How Genetic Mutations May Cause Type 1 Diabetes
The new molecular understanding could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.
Monday, May 03, 2010
Team Led by Scripps Research Scientists Develops Technique to Determine Ethnic Origin of Stem Cell Lines
Cells more representative of U.S. and world population could lead to more accurate research and safer, effective therapites.
Monday, January 04, 2010
Scripps Researchers Identify Novel Hepatitis C Inhibitors
New inhibitors have the potential to substantially widen the current options to treat HCV infection.
Thursday, December 24, 2009
Paper Finds Microdroplet PCR Enrichment Ideal Targeted Sequencing Solution for Large-Scale Population Studies
UCSD study evaluated microdroplet PCR’s advantages in performing sequence enrichment for targeted sequencing over traditional PCR approach.
Thursday, November 05, 2009
Team Led by Scripps Research Scientists Finds new Way that Cells Fix Damage to DNA
Proteins responsible for this type of DNA repair may also limit the effectiveness of chemotherapy agents, which aim to injure tumor DNA.
Monday, June 15, 2009
Scientific News
Drug May Prevent Life-Threatening Muscle Loss in Advanced Cancers
New data describes how an experimental drug can stop life-threatening muscle wasting (cachexia) associated with advanced cancers and restore muscle health.
Chemical Design Made Easier
Rice University scientists prepare elusive organocatalysts for drug and fine chemical synthesis.
Nanocarriers May Carry New Hope for Brain Cancer Therapy
Berkeley lab researchers develop nanoparticles that can carry therapeutics across the brain blood barrier.
Potential Persistent Tuberculosis Treatment
Researchers have discovered several first-in-class compounds that target hidden TB infections by attacking a critical process the bacteria use to survive in the hostile environment of the lungs.
Shedding Light on “Dark” Cellular Receptors
UNC and UCSF labs create a new research tool to find homes for two orphan cell-surface receptors, a crucial step toward finding better therapeutics and causes of drug side effects.
Giant Molecules Inhibit Ebola Infection
European researchers have designed a "giant" molecule formed by thirteen fullerenes covered by carbohydrates which, by blocking this receptor, are able to inhibit the cell infection by an artificial ebola virus model.
First Therapy Appearing to Reverse Decline in Parkinson’s
An FDA-approved drug for leukemia improved cognition, motor skills and non-motor function in patients with Parkinson’s disease and Lewy body dementia in a small clinical trial, say researchers at Georgetown University Medical Center (GUMC).
Fighting Pain with Ketamine
Researchers at the Texas A&M Health Science Center are using ketamine, a drug that already exists as an anesthetic, to treat pain.
Possible New Treatment for Neurodegenerative Diseases Found
Researchers at the University of Liverpool have found that a well-established anti-epileptic drug could also be used as a treatment for neurodegenerative diseases.
Breast Cancer Drug Beats Superbug
Tamoxifen helps white blood cells clear multidrug-resistant bacteria in lab and mouse studies.
Skyscraper Banner

SELECTBIO Market Reports
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
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos