New Agent Shows Potential in Battling Renal Cancer

Chemists have developed a substance in the laboratory that has potential applications in fighting renal cancer.

The compound, called IR-199, targets the proteasome, a cellular complex in renal cancer cells, similar to the way the drug bortezomib, approved by the US Food and Drug Administration, targets and blocks the proteasome in multiple myeloma cells, a cancer that arises in bone marrow.

Dr. Michael Pirrung, a distinguished professor of chemistry at the University of California, Riverside (USA;), reported on the findings on the development of TIR-199 on February 19, 2013, at the 5th International Conference on Drug Discovery and Therapy, held in Dubai (UAE).

Functioning similar to a cellular garbage dump, the proteasome degrades proteins. Agents that suppress the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a range of cancer cell lines, although with varied results. Bortezomib, for instance, although effective against multiple myeloma, has numerous side effects because cells other than bone marrow cells are affected. “The novel feature of our new proteasome inhibitor, TIR-199, is that it is nearly as potent as bortezomib, but is selective in inhibiting the growth of only renal cancer cell lines,” Dr. Pirrung said. “It’s what makes TIR-199 attractive.”

The TIR-199 project at UC Riverside began approximately four years ago after a multidisciplinary, international group of scientists reported on a class of compounds that act on the proteasome. These compounds are the “syringolin” natural products—such as a compound generated 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,” Dr. Pirrung said. “Of the two, TIR-199 showed most promise.”

Dr. Pirrung’s laboraroty first shipped TIR-199 samples to the University of Hawaii, Hilo, where Dr. André Bachmann, an associate professor of pharmaceutical sciences and Dr. Pirrung’s collaborator, researched TIR-199 in assays for how it worked against the proteasome. Dr. Bachmann then tested the compound against a limited number of cancer cell lines that demonstrated that TIR-199 was effective against the cancer cells. However, it still is not known, however, was if TIR-199 was toxic to normal cells.

Encouraged by these results, Dr. Pirrung submitted TIR-199 samples to the National Cancer Institute at the US National Institutes of Health (Bethesda, MD, USA), where the compound was subjected to a stringent 60-cell screening used typically to assess compounds for their effectiveness in fighting 60 types of cancer, including lung, leukemia, 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 cancer,” Dr. Pirrung said. “This is good news also because the NCI scientists told us there really are no good drugs out there to fight renal cancer.”

In the next phase, the NCI will evaluate TIR-199 on cells cultured in a hollow fiber that partially imitates the body by providing a three-dimensional (3D) setting. If the test findings are promising, TIR-199 will be assessed on lab mice.

The UCR Office of Technology Commercialization has filed a patent application on TIR-199 and is currently looking for collaborators 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,” Dr. 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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University of California, Riverside