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Nature DOI:10.1038/s41586-020-2925-1

Small-molecule-induced polymerization triggers degradation of BCL6.

Publication TypeJournal Article
Year of Publication2020
AuthorsSłabicki, M, Yoon, H, Koeppel, J, Nitsch, L, Burman, SSRoy, 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
Date Published2020 12
KeywordsCryoelectron Microscopy, Humans, In Vitro Techniques, Ligands, Models, Molecular, Nuclear Proteins, Polymerization, Proteasome Endopeptidase Complex, Proteolysis, Proto-Oncogene Proteins c-bcl-6, Solvents, Synthetic Biology, Ubiquitin-Protein Ligases, Ubiquitination

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 targets, but a substantial subset of proteins are resistant to targeted degradation using existing approaches. 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 BCL6. 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.


Alternate JournalNature
PubMed ID33208943
PubMed Central IDPMC7816212
Grant ListR35 CA253125 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
F99 CA253754 / CA / NCI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
R01 CA214608 / CA / NCI NIH HHS / United States
R01 CA218278 / CA / NCI NIH HHS / United States