Nav: Home

Clues for drugging the 'undruggable'

November 05, 2018


Most FDA-approved small molecule drugs inhibit enzymes - biology's protein machines that catalyze chemical reactions. However, many proteins in biology are not enzymes, but they nonetheless play critical roles in health and disease. Among these, transcription factors are particularly interesting drug targets because they act as the on/off switches of gene expression, processes that can cause developmental diseases and cancer when they go wrong.

Until recently, transcription factors have been considered 'undruggable' because they lack catalytic active sites for drugs to bind. But in 2014, thalidomide and its analogs - important treatments for multiple myeloma and other blood cancers - were found to inactivate transcription factors using a previously unknown mode of action. These drugs did not inhibit the function of their target proteins, but instead recruited them to an E3 ubiquitin ligase, which flags proteins as garbage causing their removal by the waste disposal system of the cell.

In their recent study, published in Science, Thomä's and Ebert's teams have explored whether other transcription factors could be degraded by a similar mechanism. Their results show that modifications to thalidomide result in degradation of different zinc finger transcription factors - a first step towards designing future drugs.


In their recent study, the researchers traced this new mode of action to one critical zinc finger in the degraded transcription factors. A zinc finger is a small protein domain held together by a zinc ion; zinc finger domains typically act as interaction modules to bind DNA, RNA or other proteins. More than 800 zinc finger containing proteins - which together comprise over 6,500 individual zinc finger domains - exist in humans, making up the biggest class of putative transcription factors.

Having found that a single zinc finger domain was sufficient to make a specific transcription factor susceptible to drug-mediated degradation, the researchers investigated whether other such examples existed. By creating a library of all known zinc finger domains from humans and linking them to a fluorescent protein stability marker, the researchers identified a total of 11 zinc finger motifs that led to degradation in cells. "11 out of 6,500 zinc fingers was a good start," explains Georg Petzold, a postdoc in the Thomä lab and one of the two first authors of the study, "but protein degradation is a multi-step process and recruitment to the E3 ubiquitin ligase does not necessarily lead to degradation."

So the researchers examined the step preceding zinc finger degradation - recruitment to the CRL4-CRBN ubiquitin ligase - and identified another 150 additional zinc fingers that bind the ligase in vitro. "Although these zinc fingers were not degraded in cells, these results were exciting because they extended the number of potential targets to many more than just the first 11," explains Nicolas Thomä.


Surprisingly, their structural analysis revealed that specificity between the drug and a zinc finger could depend on as little as one amino acid that formed a side chain contact with the drug, presenting an opportunity to design drugs that could target different zinc fingers. To test this hypothesis, the researchers repeated the cellular screen with two more recent thalidomide derivatives and found that these different drugs degraded distinct sets of zinc fingers.

"We not only identified new thalidomide analog targets, but also showed that it might be possible to create compounds that selectively degrade certain zinc fingers," says Petzold. "The zinc finger library screens are good schemes to screen for such compounds; there is a lot of potential for drug development!"

Dr Nicolas Thomä,,
Tel: + 41 (0)61 697 86 30


Quinlan L. Sievers*, Georg Petzold*, Richard D. Bunker, Aline Renneville, Miko?aj S?abicki, Brian Liddicoat, Wassim Abdulrahman, Tarjei Mikkelsen, Benjamin L. Ebert, Nicolas H. Thomä (2018) Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN Science. DOI: 10.1126/science.aat0572.
* These authors contributed equally to this work.


Nicolas Thomä is a Senior Group Leader at the FMI. He is interested in the machinery that controls the integrity of the DNA. He combines X-ray crystallography and cryo-electron microscopy with biochemical and biophysical studies to better understand large protein complexes involved in crucial cellular functions such as DNA repair, telomere maintenance and epigenetics in health and disease.
» More about Nico Thomä


The Friedrich Miescher Institute for Biomedical Research (FMI), based in Basel, Switzerland, is a world-class center for basic research in life sciences. It was founded in 1970 as a joint effort of two Basel-based pharmaceutical companies and continues to receive, now as an independent foundation, financial support from Novartis. The FMI is devoted to the pursuit of fundamental biomedical research. Areas of expertise are neurobiology, quantitative biology, and the epigenetics of stem cell development and cell differentiation. The FMI also offers training in biomedical research to PhD students and postdoctoral fellows from around the world The institute counts 340 collaborators and is affiliated with the University of Basel as well as with the Novartis Institutes for BioMedical Research. The Director of the FMI since 2004 is Prof. Susan Gasser.

Friedrich Miescher Institute

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at