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Drug discovery: New method identifies E3-specific degraders for targeted therapies


Alexander Hanzl and Georg Winter (© Laura Alvarez / CeMM).

For many years, the team of Principal Investigator Georg Winter at CeMM has been researching the development of Targeted Protein Degraders: a new generation of drugs that achieve greater therapeutic success through the targeted degradation of harmful, pathogenic proteins. In their current study, published in the Journal of the American Chemical Society (JACS), the researchers present a new method for the identification of molecules that could act as degraders and thus be used as therapeutic drugs.

The latest generation of drugs relies on targeted degradation of damaged or pathogenic proteins. This involves the use of chemical molecules that link a damaged, pathogenic protein to the cellular waste disposal system, a so-called E3 ubiquitin ligase. This approach is also called "Targeted Protein Degradation (TPD)". The JACS study is significant to the TPD field as it overcomes an important limitation to the field, namely that the currently known degradation molecules only bind to a handful of E3 ligases, thus limiting the therapeutic options and potential. Georg Winter, Principal Investigator at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, explains: "There are about 600 E3 ligases in a human cell. We are looking for a way to find a suitable degradation molecule, for as many of these E3 ligases as possible This may open up new therapeutic pathways, especially for patients whose therapy is no longer effective due to drug resistance." In their study, first author Alexander Hanzl from Winter’s group at CeMM and his colleagues demonstrate a method that makes it possible to find suitable degrader molecules specifically for a particular E3 ligase. "Let's assume that in a certain type of cancer, one of the 600 E3 ligases is particularly abundant. Then it would be of great advantage to find a degrader that can recruit exactly this E3 ligase and thus specifically treat the cancer cells," Hanzl said.

Self-degradation mechanism of the E3 ligase makes degrader recognizable

The researchers have built upon the knowledge that   cullin-RING-E3 ligase (CRL) regulation, has a "self-degradation mechanism". Hanzl and Winter show how adding degraders and inhibitors to an E3 ligase can identify new, specific degradation molecules. "In this way, within three to six days, about 10,000 molecules can be screened for their mode of action as degraders for a specific E3 ligase," Hanzl says. Georg Winter adds:
"With more and more clinical studies on the efficacy of degraders, it is becoming apparent that, over time, therapy resistance can emerge that differs from previously described resistance mechanisms in therapies with traditional inhibitor-based drugs. It is therefore all the more important to be able to recruit as many E3 ligases as possible in order to be able to pursue new therapeutic approaches. With our study, we take a step in this direction and present the first scalable approach for finding E3 ligase selective degradation molecules."

Significantly increase efficacy

Currently, numerous degrader drugs are being tested in clinical trials, and some are already available to patients, particularly for various blood cancers. "Traditional therapeutics, which take the approach of blocking an isolated function of a protein, only reach about 20 percent of our proteins. The other 80 percent do not have a suitable binding site and thus cannot be tapped. We see great potential in the new generation of drugs using degraders for targeted protein degradation that can be significantly increased here and perhaps reach up to 80 percent of proteins in the future," says Winter. To overcome emerging resistance, it is important to be able to recruit as many E3 ligases as possible with degraders and thus ensure the "removal" of damaged proteins.
The study results demonstrate a method that enables the identification of degraders for certain E3 ligases, thus advancing the development of improved therapies.

The study “E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance” was published in the Journal of the American Chemical Society on 5 January 2023, DOI: 10.1021/jacs.2c10784

Authors: Alexander Hanzl, Eleonora Barone, Sophie Bauer, Hong Yue, Radosław P. Nowak, Elisa Hahn, Eugenia V. Pankevich, Anna Koren, Stefan Kubicek, Eric S. Fischer, und Georg E. Winter*

Funding: The Winter lab is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 851478), as well as by funding from the Austrian Science Fund (FWF, projects P32125, P31690 and P7909).