Small-molecule-induced polymerization triggers degradation of BCL6

Mikołaj Słabicki, Hojong Yoon, Jonas Koeppel, Lena Nitsch, Shourya S. Roy Burman, Cristina Genua, Katherine A. Donovan, Adam S. Sperling, Moritz Hunkeler, Jonathan M. Tsai, Rohan Sharma, Andrew Guirguis, Charles Zou, Priya Chudasama, Jessica A. Gasser, Peter G. Miller, Claudia Scholl, Stefan Fröhling, Radosław P. Nowak, Eric S. Fischer () and Benjamin L. Ebert ()
Additional contact information
Mikołaj Słabicki: Broad Institute of MIT and Harvard
Hojong Yoon: Dana-Farber Cancer Institute
Jonas Koeppel: Broad Institute of MIT and Harvard
Lena Nitsch: Broad Institute of MIT and Harvard
Shourya S. Roy Burman: Dana-Farber Cancer Institute
Cristina Genua: Broad Institute of MIT and Harvard
Katherine A. Donovan: Dana-Farber Cancer Institute
Adam S. Sperling: Broad Institute of MIT and Harvard
Moritz Hunkeler: Dana-Farber Cancer Institute
Jonathan M. Tsai: Broad Institute of MIT and Harvard
Rohan Sharma: Dana-Farber Cancer Institute
Andrew Guirguis: Broad Institute of MIT and Harvard
Charles Zou: Dana-Farber Cancer Institute
Priya Chudasama: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Jessica A. Gasser: Broad Institute of MIT and Harvard
Peter G. Miller: Broad Institute of MIT and Harvard
Claudia Scholl: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Stefan Fröhling: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Radosław P. Nowak: Dana-Farber Cancer Institute
Eric S. Fischer: Dana-Farber Cancer Institute
Benjamin L. Ebert: Broad Institute of MIT and Harvard

Nature, 2020, vol. 588, issue 7836, 164-168

Abstract: Abstract Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets1–3, but a substantial subset of proteins are resistant to targeted degradation using existing approaches4,5. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL66. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2925-1 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:588:y:2020:i:7836:d:10.1038_s41586-020-2925-1

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2925-1

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().