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000165971 1001_ $$00000-0001-6317-9296$$aSłabicki, Mikołaj$$b0$$eFirst author
000165971 245__ $$aSmall-molecule-induced polymerization triggers degradation of BCL6.
000165971 260__ $$aLondon [u.a.]$$bNature Publ. Group52462$$c2020
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000165971 500__ $$a#EA:B340#2020 Dec;588(7836):164-168
000165971 520__ $$aEffective 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.
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000165971 7001_ $$00000-0002-6062-5489$$aYoon, Hojong$$b1
000165971 7001_ $$0P:(DE-He78)e1ead319ffbadb46745d1edb5363dcb3$$aKoeppel, Jonas$$b2
000165971 7001_ $$0P:(DE-He78)b9dfd9f8f924f26c3f2bad89ee6d7f60$$aNitsch, Lena$$b3$$udkfz
000165971 7001_ $$00000-0001-9274-9104$$aRoy Burman, Shourya S$$b4
000165971 7001_ $$aDi Genua, Cristina$$b5
000165971 7001_ $$00000-0002-8539-5106$$aDonovan, Katherine A$$b6
000165971 7001_ $$aSperling, Adam S$$b7
000165971 7001_ $$00000-0003-0246-1188$$aHunkeler, Moritz$$b8
000165971 7001_ $$aTsai, Jonathan M$$b9
000165971 7001_ $$aSharma, Rohan$$b10
000165971 7001_ $$00000-0003-3134-0596$$aGuirguis, Andrew$$b11
000165971 7001_ $$aZou, Charles$$b12
000165971 7001_ $$0P:(DE-He78)97208bef945f0ab6bf33ed9925685de4$$aChudasama, Priya$$b13$$udkfz
000165971 7001_ $$aGasser, Jessica A$$b14
000165971 7001_ $$aMiller, Peter G$$b15
000165971 7001_ $$0P:(DE-He78)2c1a21d1cf5fdc9e297512c9d1354250$$aScholl, Claudia$$b16$$udkfz
000165971 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b17$$udkfz
000165971 7001_ $$00000-0002-0605-0071$$aNowak, Radosław P$$b18
000165971 7001_ $$00000-0001-7337-6306$$aFischer, Eric S$$b19
000165971 7001_ $$00000-0003-0197-5451$$aEbert, Benjamin L$$b20
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