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Roy Burman, Shourya

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Roy Burman

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Shourya

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Roy Burman, Shourya

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Author's Publications: search.filters.isAuthorOfPublication.85a2c570-67b8-43d1-8b17-21a618579613

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    Small-molecule-induced polymerization triggers degradation of BCL6
    (Springer Science and Business Media LLC, 2020-11-18) Słabicki, Mikołaj; Yoon, Hojong; Koeppel, Jonas; Nitsch, Lena; Roy Burman, Shourya; Di Genua, Cristina; Donovan, Katherine A.; Sperling, Adam S.; Hunkeler, Moritz; Tsai, Jonathan M.; Sharma, Rohan; Guirguis, Andrew; Zou, Charles; Chudasama, Priya; Gasser, Jessica A.; Miller, Peter G.; Scholl, Claudia; Fröhling, Stefan; Nowak, Radosław P.; Fischer, Eric S.; Ebert, Benjamin L.
    Effective and sustained inhibition of non-enzymatic oncogenic driver proteins represents a major pharmacologic challenge. The clinical success of thalidomide analogs demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets1-3, but a significant subset of proteins are recalcitrant to targeted protein degradation using current approaches4,5. Here we report an alternative mechanism, whereby a small molecule induces highly specific, reversible polymerization, sequestration into cellular foci, and subsequent degradation of a target protein. BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation6. We used cryo-EM to reveal how the solvent-exposed moiety of a BCL6 inhibitor 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 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to superior pharmacological activity. These findings create new avenues for the development of therapeutics and synthetic biology.