Targeting cancer proteins for degradation

February 24, 2016, Friedrich Miescher Institute for Biomedical Research
Targeting cancer proteins for degradation

Cancer research is increasingly focusing on therapeutic approaches in which disease causing proteins are marked for early degradation. Nicolas Thomä and his group at the Friedrich Miescher Institute for Biomedical Research have now shown how pharmaceutical compounds hijack an ubiquitin ligase to target such proteins for degradation. This new mechanism could provide opportunities for targeted degradation of cancer proteins.

During the last decade, cancer researchers have been seeking to exploit the cellular "waste disposal system" to induce of proteins that cause or promote cancer. To trigger degradation, cellular proteins need to be labeled with a disposal tag, which is achieved by the activity of so called enzymes. Therefore, researchers have pursued various strategies for rendering disease-causing proteins susceptible to the action of ubiquitin ligases and thus inducing degradation.

In a study published today in Nature, Nicolas Thomä, a group leader at the Friedrich Miescher Institute for Biomedical Research (FMI), and co-workers have now shown that small pharmaceutical molecules (compounds) destabilize specific cancer proteins by gluing them to an ubiquitin ligase. Thomä comments: "This is a new mode of action for a therapeutic agent, as it induces selective degradation of specific targets rather than inhibiting enzymatic function. It also represents a new emerging paradigm in pharmacology, and we now see for the first time how this works on the molecular level."

The scientists described this new mechanism by investigating the thalidomide derivative lenalidomide. This drug is clinically effective in the treatment of blood cancers such as multiple myeloma and myelodysplastic syndrome, where it induces degradation of various cancer-associated proteins, including casein kinase 1α (CK1α). However, it remained unclear how lenalidomide alters the specificity of the relevant ubiquitin ligase complex so that CK1α is marked for degradation.

By elucidating the crystal structure of DDB1–CRBN bound to lenalidomide and CK1α, first author Georg Petzold (a postdoc in Thomä's group) showed that lenalidomide enables the binding of CK1α. Petzold explains: "In the ubiquitin ligase complex, CRBN is responsible for recruiting substrates. We found that lenalidomide binding to CRBN creates a neomorphic interface that is necessary to bind CK1α."

In the case of lenalidomide, the efficacy of the drug is based on inducing the destruction of disease causing enzymes rather than inhibiting its . Thomä says: "By observing how a small molecule glues a to an ubiquitin ligase, we now have a blueprint that will help develop new small molecule therapeutics that work by a related mechanism and could be applied to other diseases."

Explore further: Mechanism of action of thalidomide elucidated

More information: Petzold G, Fischer ES, Thomä NH (2016) Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature [Epub ahead of print]

Related Stories

Mechanism of action of thalidomide elucidated

July 17, 2014
(Medical Xpress)—Scientists led by Nicolas Thomä at the Friedrich Miescher Institute for Biomedical Research have clarified the workings of thalidomide at the molecular level. Their analysis of various structures, published ...

Study reveals how lenalidomide fights cancer and treats blood syndrome

July 2, 2015
(Medical Xpress)—A team of researchers with member affiliations to institutions in the U.S. and Germany has uncovered the mechanism by which a cancer fighting drug reduces cancer cells and also helps patients with a blood ...

Recommended for you

New imaging technique can spot tuberculosis infection in an hour

August 16, 2018
Guided by glowing bacteria, researchers have devised an imaging technique that can diagnose live tuberculosis in an hour and help monitor the efficacy of treatments. That's particularly critical because many TB strains have ...

Obesity, infertility and oxidative stress in mouse egg cells

August 16, 2018
Excessive body fat is associated with negative effects on female fertility and pregnancy. In mice, maternal obesity impairs proper development of egg precursor cells called oocytes. In a recent paper published in Molecular ...

Research shows it's possible to reverse damage caused by aging cells

August 15, 2018
What's the secret to aging well? University of Minnesota Medical School researchers have answered it- on a cellular level.

This matrix delivers healing stem cells to injured elderly muscles

August 15, 2018
A car accident leaves an aging patient with severe muscle injuries that won't heal. Treatment with muscle stem cells from a donor might restore damaged tissue, but doctors are unable to deliver them effectively. A new method ...

Male tobacco smokers have brain-wide reduction of CB1 receptors

August 15, 2018
Chronic, frequent tobacco smokers have a decreased number of cannabinoid CB1 receptors, the "pot receptor", when compared with non-smokers, reports a study in Biological Psychiatry.

Byproducts of 'junk DNA' implicated in cancer spread

August 14, 2018
The more scientists explore so-called "junk" DNA, the less the label seems to fit.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.