New compound holds high promise in battling kidney cancer

February 19, 2013
New compound holds high promise in battling kidney cancer
This image shows the compound TIR-199 that holds much promise in the laboratory in fighting renal (kidney) cancer. Credit: Pirrung Lab, UC Riverside.

Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (kidney) cancer.

Named TIR-199, the compound targets the "proteasome," a cellular complex in cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple , a cancer coming from bone marrow.

Michael Pirrung, a distinguished professor of chemistry at UC Riverside, announced the development of TIR-199 in a lecture he gave on Feb. 19 at the 5th International Conference on Drug Discovery and Therapy, held in Dubai, UAE.

Operating like the garbage dump of a cell, the proteasome breaks down proteins. Drugs that block the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a variety of cancer cell lines, albeit with mixed results. For example, bortezomib, though effective against , has many side effects because cells other than are affected.

"The novel feature of our new , TIR-199, is that it is nearly as potent as , but is selective in inhibiting the growth of only renal cancer cell lines," Pirrung said. "It's what makes TIR-199 attractive."

The TIR-199 research project at UC Riverside began about four years ago after a multidisciplinary, international team reported on a class of compounds that act on the proteasome. These compounds are the "syringolin" natural products—such as a compound produced naturally by the wheat-infecting bacterium Pseudomonas syringae. TIR-199 is a synthetic relative of syringolin.

"At UCR we began to work on, and completed the synthesis of, two compounds from this class of compounds," Pirrung said. "Of the two, TIR-199 showed most promise."

Pirrung's lab first shipped TIR-199 samples to the University of Hawaii, Hilo, where André Bachmann, an associate professor of pharmaceutical sciences and Pirrung's collaborator, studied TIR-199 in test-tube assays for how it worked against the proteasome. Bachmann then tested the compound against a limited number of cancer that showed that TIR-199 was effective against the . What remained unclear, however, was if TIR-199 was toxic to normal cells.

Encouraged by these results, Pirrung submitted TIR-199 samples to the National Cancer Institute at the National Institutes of Health, where the compound was subjected to a rigorous 60-cell screening used routinely to test compounds for their effectiveness in battling 60 kinds of cancer, including leukemia, lung, colon, brain, breast, ovarian prostate and renal cancers.

"We were very excited when the NCI informed us that TIR-199 has excellent potential to be moved to drug development because of its selective activity against renal ," Pirrung said. "This is good news also because the NCI scientists told us there really are no good drugs out there to fight ."

Next, the NCI will test TIR-199 on cells grown in a hollow fiber that partially mimics the body by offering a three-dimensional environment. If the test results are positive, TIR-199 will be tested on mice.

The UCR Office of Technology Commercialization has filed a patent application on TIR-199 and is currently seeking partners in industry interested in developing the compound commercially. Several biotechnology companies have already shown interest.

"We still have to fine-tune TIR-199 in the lab because some aspects—certain structural elements within it—make it easily metabolized," Pirrung said. "But now that we have a good handle on how structural changes in the compound affect anticancer activity and how the parent drug binds to the proteasome, we are pretty confident of making a better version—the second generation—of TIR-199."

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