Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (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
Named TIR-199, the compound targets the "proteasome," a cellular complex in kidney cancer cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple myeloma cells, 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 multiple myeloma, has many 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," 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 cell lines that showed that TIR-199 was effective against the cancer cells. 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 cancer," 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."
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."
The project was funded by a grant from the University of California Institute for Mexico and the United States (UC MEXUS), to Tannya Ibarra-Rivera, a former postdoctoral researcher in Pirrung's lab who helped discover TIR-199 and after whose initials the compound is named; and to Pirrung from the UC Cancer Research Coordinating Committee.
The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR's enrollment has exceeded 21,000 students. The campus will open a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual statewide economic impact of more than $1 billion. A broadcast studio with fiber cable to the AT&T Hollywood hub is available for live or taped interviews. UCR also has ISDN for radio interviews. To learn more, call (951) UCR-NEWS.
Iqbal Pittalwala | EurekAlert!
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
07.12.2016 | Materials Sciences
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering