New mechanism of action: A small-molecule degrades a cancer-promoting protein by gluing it into filaments
“Molecular glue degraders” are a new class of cancer drugs, which “glue” cancer growth-promoting proteins directly to the molecular machinery of a cell’s disposal system, leading to the subsequent degradation of the cancer-driving proteins and anti-tumor activity. Scientists from Heidelberg and USA have now deciphered another mechanism whereby a small molecule can degrade a cancer protein.
“Molecular glue degraders” are a new class of cancer drugs, which “glue” cancer growth-promoting proteins directly to the molecular machinery of a cell’s disposal system, leading to the subsequent degradation of the cancer-driving proteins and anti-tumor activity. Scientists from Heidelberg and USA have now deciphered another mechanism whereby a small molecule can degrade a cancer protein. This drug binds to the lymphoma-driving protein BCL6, and induces BCL6 self-polymerization, which then attracts the cell's disposal system, leading to BCL6 degradation and the death of the cancer cell. The research results open up new paths in drug development for the treatment of cancer.
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital (UKHD) and the German Cancer Aid (DKH).
Most targeted cancer drugs used clinically are small molecules that inhibit the activity of growth-promoting proteins. In recent years, many such cancer-promoting proteins have been identified. However, of all known cancer drivers, only a few offer suitable targets for these drugs. A central challenge for cancer research is therefore the search for new therapeutic approaches. "Molecular glue degraders" hold promise to expand the repertoire of cancer targets. This class of the drugs induce interactions between a protein and components of the cellular waste disposal system. The best-known drug of this type is Lenalidomide, which is approved in Germany for the treatment of certain types of blood cancer, including multiple myeloma and myelodysplastic syndrome.
Researchers at the German Cancer Research Center (DKFZ), the National Center for Tumor Diseases (NCT) in Heidelberg, the Broad Institute of MIT and Harvard University in Cambridge, and the Dana-Farber Cancer Institute in Boston have now uncovered another mechanism of a drug molecule from the group of "molecular glue degraders." The increased occurrence of BCL6 in a cell is involved in the development of a certain form of lymph gland cancer, which makes BCL6 a suitable candidate for targeted drugs. In the search for a BCL6 inhibitor, the pharmaceutical company Boehringer Ingelheim has identified a small molecule that binds to BCL6 and induces the degradation of BCL6, so that the lymphoma cells die.
"To track what happens to BCL6 after treatment with the degrader, we labeled BCL6 and observed the appearance of BCL6-containing foci under the microscope within minutes of treatment, followed by their disappearance, presumably caused by protein degradation" explains Jonas Koeppel, one of the study's lead authors. „This sequence of events hinted at a drug mechanism that involved BCL6 self-interactions," adds co-author Lena Nitsch.
A crucial discovery in the elucidation of the mechanism was the fact that BCL6 formed long fibers, so-called helical protein filaments, when treated with the new substance. Research led by Hojong Yoon, a PhD student at Harvard Medical School and the Dana-Farber Cancer Institute, resolved the molecular structure of the helical filaments using the scientific method of cryo electron microscopy. The structure showed that the drug binds to a groove on the BCL6 protein and then triggers an interaction with a second, neighboring BCL6 protein. In this way, the novel drug molecule “glues” individual BCL6 molecules together in the filament structure. This is referred to as polymerization.
"This is the first study that demonstrates how a small molecule can inactivate cancer-causing proteins by inducing polymerization and subsequent proteasomal degradation," says Mikolaj Slabicki, lead author of the study. The ultimate goal is to identify more small molecules that work through a similar mechanism and to learn principles to design compounds that would target other dysregulated proteins.”
"I am incredibly proud that young scientists in our department - Mikolaj Slabicki, Jonas Koeppel and Lena Nitsch - have succeeded in making such a fundamental discovery, and I am pleased to be part of this transatlantic collaboration," said Stefan Fröhling, Head of the Department of Translational Medical Oncology at DKFZ, Managing Director of the NCT Heidelberg and co-author of the study.
The study was co-facilitated by Benjamin Ebert, Head of the Department of Medical Oncology at the Dana-Farber Cancer Institute and recipient of the 2019 Meyenburg Cancer Research Award, and Eric Fischer, Associate Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School.
Słabicki M*, Yoon H*, Koeppel J*, Nitsch L, Burman SSR, Di Genua C, Donovan KA, Sperling AS, Hunkeler M, Tsai JM, Sharma R, Guirguis A, Zou C, Chudasama P, Gasser JA, Miller PG, Scholl C, Fröhling S, Nowak RP, Fischer ES , Ebert BL. Small molecule-induced polymerization triggers degradation of BCL6. Nature, https://doi.org/10.1038/s41586-020-2925-1
*These authors contributed equally
Animation of mechanism of action: https://youtu.be/bF87oA4RWZ4
Concept and copyright: Mikolaj Slabicki, Hojong Yoon, Jonas Koeppel, Animation: JumpStartVideo.net
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Legend: Mechanism of action of the new molecule of the "molecular glue degrader" group.
Legend: The study shows how a small molecule can inactivate cancer-causing proteins by inducing the formation of long protein chains - a polymerization.
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National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital (UKHD) and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. This is true for diagnosis and treatment, follow-up care or prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here, the patients benefit from an individual treatment plan prepared in interdisciplinary expert rounds, so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. Since 2015, the NCT Heidelberg has maintained a partner site in Dresden. The Hopp Children's Cancer Center (KiTZ) was established in Heidelberg in 2017. The pediatric oncologists at KiTZ work together in parallel structures with the NCT Heidelberg.
German Cancer Research Center (DKFZ)
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.
Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
Heidelberg University Hospital (UKHD)
Heidelberg University Hospital (UKHD) is one of the most important medical centers in Germany; Heidelberg University's Medical Faculty is one of Europe's most prestigious biomedical research facilities. Their shared objective is the development of innovative diagnostics and treatments and their prompt implementation for the benefit of the patient. The hospital and faculty employ approximately 13,000 individuals and are involved in training and qualification. Every year approximately 65,000 patients are treated as inpatients and 56,000 as day patients in more than 50 specialized clinical departments with around 2,000 beds, with more than 1 million patients being treated as outpatients. Together with the German Cancer Research Center and German Cancer Aid, the Heidelberg University Hospital established The National Center for Tumor Diseases (NCT) Heidelberg as the leading oncology center of excellence in Germany. The Heidelberg Curriculum Medicinale (HeiCuMed) is at the forefront of medical training in Germany. At present 3,700 aspiring physicians and doctors are studying in Heidelberg.
Mikolaj Slabicki, Jonas Koeppel, Lena Nitsch, stefan Froehling