Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Wrong proteins targeted in battle against cancer?

02.10.2002


Lasker recipient James E. Darnell contends drug developers should focus more on ’transcription factor’ proteins



Researchers may be looking for novel cancer drugs in the wrong places, says Rockefeller University Professor James E. Darnell, Jr., M.D., in an article in this month’s Nature Reviews Cancer.

Darnell, who received the 2002 Albert Lasker Award for Special Achievement in Medical Science, argues that drug development research should focus more on a specific group of proteins - called transcription factors - known to be overactive in almost all human cancers.


"The facts indicate that a limited number of transcription factors are indeed overactive in many cancers and that these overactive proteins themselves are appropriate drug targets," says Darnell, head of the Laboratory of Molecular Cell Biology at Rockefeller and co-author of the popular textbook Molecular Cell Biology.

These transcription factors include STAT3, discovered by Darnell and colleagues in 1994, STAT5, NF-kappaB, B-catenin, Notch, GLI and c-JUN - all of which play significant roles in a wide variety of cancers.

According to Darnell, drug developers continue to largely ignore these seemingly universal molecules of cancer because, unlike other cancer-causing proteins called protein kinases, transcription factors do not posses "active sites" or pockets that can be easily fitted with small inhibitory drugs.

Instead, drugs designed against transcription factors would have to target protein-protein interactions - which, because of their larger surface areas, are much harder to disrupt.

Still, Darnell argues that, despite inherent obstacles, such an approach could potentially yield novel cancer therapeutics.

"After all," he asks, "What is the benefit to medicine in all the twenty-first century promise of proteomics if we cannot selectively inhibit protein-protein interactions?"

Many of the transcription factors involved in cancer normally allow a healthy cell to respond to signals from the external environment by activating the "expression" of certain genes, which then leads to the production of new proteins. In cancer - which is characterized by cell growth gone awry - genetic mutations cause these proteins, also referred to as "oncogenic proteins," to become unusually active.

Therefore, drugs designed to block or decrease their surplus activity might effectively treat this disease.

"Transcription factors are attractive targets because they are both less numerous than other signaling activators and are at a focal point of many cancer pathways," says Darnell.

"Like kicking Achilles in the heel, striking at these targets would constitute a more global approach to fighting cancer."

In the past, drug developers in search of cancer therapeutics have placed a large focus on cancer-causing molecules called protein kinases, primarily because their active sites - tiny crevices where small molecules normally bind and activate the protein - can be easily blocked with small molecule drugs. The drug Gleevec, for example, can temporarily treat chronic myeloid leukemia by fitting into and plugging up the active site of a protein kinase, called the Ableson kinase, associated with this disease.

But, according to Darnell, this approach has two main drawbacks. First, as is the case with Gleevec, resistance to the drugs can develop, and, second, each of the protein kinases tends to be associated with only a limited number of cancer types.

Darnell argues that both of these obstacles could possibly be overcome by instead targeting certain transcription factors. He says that these proteins should not develop resistance to drugs as fast as protein kinases, and, because they are common to many cancers, drugs designed to block them should work against a diverse range of cancer types.

The final challenge is then how to target molecules that lack the convenient active sites of protein kinases. Drugs directed against transcription factors would have to prevent them from binding to one of their two primary molecular targets: DNA or proteins. To turn on specific genes, transcription factors must bind to other proteins as well as to DNA.

Since past efforts to develop drugs that disrupt DNA-protein interactions have failed, Darnell believes that targeting protein-protein interactions is the next logical step.

"With the availability of robotic screening procedures, huge chemical libraries need to be screened for small molecules that target any of the specific protein-protein interactions of transcription factors," he says.

"Even though this approach is more difficult," he adds, "It has proved practical in one preliminary case, and furthermore many inventive technologies from chemistry labs around the world give hope that this approach has great possibilities."

Whitney Clavin | EurekAlert!
Further information:
http://www.rockefeller.edu/

More articles from Health and Medicine:

nachricht New High-Performance Center Translational Medical Engineering
26.04.2017 | Fraunhofer ITEM

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Scientist invents way to trigger artificial photosynthesis to clean air

26.04.2017 | Materials Sciences

Ammonium nitrogen input increases the synthesis of anticarcinogenic compounds in broccoli

26.04.2017 | Agricultural and Forestry Science

SwRI-led team discovers lull in Mars' giant impact history

26.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>