Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Breakthrough finds molecules that block previously 'undruggable' protein tied to cancer

10.04.2015

A team of scientists at the University of Kansas has pinpointed six chemical compounds that thwart HuR, an "oncoprotein" that binds to RNA and promotes tumor growth. The findings, which could lead to a new class of cancer drugs, appear in the current issue of ACS Chemical Biology.

"These are the first reported small-molecule HuR inhibitors that competitively disrupt HuR-RNA binding and release the RNA, thus blocking HuR function as a tumor-promoting protein," said Liang Xu, associate professor of molecular biosciences and corresponding author of the paper.


Research at the University of Kansas has isolates six compounds that block the cancer-facilitating protein HuR.

Credit: KU News Service/University of Kansas

The results hold promise for treating a broad array of cancers in people. The researcher said HuR has been detected at high levels in almost every type of cancer tested, including cancers of the colon, prostate, breast, brain, ovaries, pancreas and lung.

"HuR inhibitors may be useful for many types of cancer," Xu said. "Since HuR is involved in many stem cell pathways, we expect HuR inhibitors will be active in inhibiting 'cancer stem cells,' or the seeds of cancer, which have been a current focus in the cancer drug discovery field."

HuR has been studied for many years, but until now no direct HuR inhibitors have been discovered, according to Xu.

"The initial compounds reported in this paper can be further optimized and developed as a whole new class of cancer therapy, especially for cancer stem cells," he said. "The success of our study provides a first proof-of-principle that HuR is druggable, which opens a new door for cancer drug discovery. Many other RNA-binding proteins like HuR, which are so far undruggable, can also be tested for drug discovery using our strategy."

The research team evaluated about 6,000 compounds from both the KU Chemical Methodologies and Library Development Center and the Food and Drug Administration in a process known as "High Throughput Screening," hunting for compounds that obstruct HuR's interface with healthy human RNA.

The KU researchers confirmed the potential of the most promising compounds with cutting-edge techniques like Amplified Luminescent Proximity Homogeneous Assay, surface plasmon resonance, ribonucleoprotein immunoprecipitation assay and luciferase reporter functional studies -- verifying that six compounds with a similar "scaffold" could be starting points of novel cancer drugs to target the oncoprotein HuR.

"A cancer-causing gene, or oncogene, makes RNA, which then makes an oncoprotein that causes cancer or makes cancer cells hard to kill, or both," Xu said. "This is the problem we're trying to overcome with precision medicine."

The scientist said the HuR-RNA binding site is like a long, narrow groove, not a well-defined pocket seen in other druggable proteins targeted by many current cancer therapies.

"HuR tightly binds to RNA like a hand," Xu said. "The HuR protein grabs the 'rope' -- or the RNA -- at a site called 'ARE' on the rope. We aimed to find a small-molecule compound that makes the hand release the rope by competing with ARE of the RNA."

The research took more than 3 1/2 years and involved the collaboration of chemists, cancer biologists, computer modeling experts, biochemists and biophysicists at KU -- notably the labs of Xu, Jeffrey Aubé in the Department of Medicinal Chemistry and Jon Tunge in the Department of Chemistry.

Grants from the National Institutes of Health, along with funding from the state of Kansas, the Hall Family Foundation and Bold Aspiration funding from KU's Office of the Provost, supported the work.

For Xu, the findings are reflective of a personal commitment to improving odds for people diagnosed with cancer, the second-largest killer in the U.S. after heart disease.

"Trained as medical doctor and Ph.D., with both a grandfather and an uncle who died of cancer, I devoted my career to cancer research and drug discovery -- aiming to translate discovery in the lab into clinical therapy, to help cancer patients and their families," he said. "We hope to find a better therapy -- and eventually a cure -- for cancer."

###

Collaborators from KU and KU Medical Center include Xiaoqing Wu, Lan Lan, David Michael Wilson, Rebecca Marquez, Wei-chung Tsao, Philip Gao, Anuradha Roy, Benjamin Andrew Turner, Peter McDonald, Jon Tunge, Steven Rogers, Dan Dixon and Jeffrey Aubé.

Media Contact

Brendan M Lynch
brendan@ku.edu
785-864-8855

 @KUNews

http://www.news.ku.edu 

Brendan M Lynch | EurekAlert!

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>