Credit: NIH
Chemists say they have determined the correct structure of a compound that has shown activity against lymphoma and a range of other cancers.
Their research, published in Angewandte Chemie, focused on a compound called TIC10.
The team showed that TIC10’s structure differs subtly from a version described by another group last year, and the previous structure associated with TIC10 actually describes a molecule that lacks TIC10’s anticancer activity.
The newly identified structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for possible therapeutic uses.
“This new structure should generate much interest in the cancer research community,” said study author Kim D. Janda, PhD, of The Scripps Research Institute in La Jolla, California.
Antitumor potential
TIC10 was first described in 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 the natural antitumor protein TRAIL. (TIC10 stands for TRAIL-inducing compound #10.)
As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper’s authors reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice.
Tumors can develop resistance to TRAIL, but Dr 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. So Dr Janda asked one of his postdoctoral researchers, Jonathan Lockner, to make TIC10 using that information.
Although the original TIC10 research team had seemingly confirmed the predicted structure with mass spectrometry, no one had 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,” Dr 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 Dr Lockner’s newly synthesized “TIC10.” When tested, it failed to induce TRAIL expression in cells, even at high doses.
“Of course, I was nervous,” Dr Lockner said. “As a chemist, you never want to make a mistake and give biologists the wrong material.”
To try and verify they had the right material, Dr 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 Lab and coauthor of the new paper.
“That prompted us to look more closely at the structures of these 2 compounds.”
The researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. They also tested the 2 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 3 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 2 compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.
And Dr 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, Dr 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, according to the researchers. The angular core of the TRAIL-inducing molecule Dr Janda’s team discovered is 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.
