To characterize the scope of drug-induced degradation by novel IMiD derivatives, we employed a library of 6,572 C2H2 zinc fingers fused with green fluorescent protein (GFP) to observe protein degradation. This approach enabled us to identify zinc finger proteins degraded by CC-122 (avadomide) and CC-220 (iberdomide). CC-122 and CC-220 resulted in the degradation of distinct and unique patterns of C2H2 zinc fingers. The zinc finger ZKSC5 was exclusively degraded by CC-122, while the zinc finger IKZF2/4 was exclusively degraded by CC-220. Those results were published in Sievers QL, Petzold G, Bunker RD, Renneville A, Słabicki M, Liddicoat BJ, Abdulrahman W, Mikkelsen T, Ebert BL, Thomä NH. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, 2018.
To identify novel molecular glue degraders, we correlated the viability data for 4,518 drugs with the expression levels of 499 E3 ligase components and identified that the toxicity of the kinase inhibitor CR8 correlates with the expression levels of an adaptor protein, DDB1. We showed that CR8 binds to CDK12 and induces a novel interaction with DDB1, resulting in the ubiquitination and degradation of CDK12 binding partner cycK. We demonstrated that this kinase inhibitor can gain glue activity by the chemical modification of the solvent exposed moiety. Our study suggest that other drugs can possess molecular glue activity. This work was published in Słabicki M*, Kozicka Z*, Petzold G*, Li Y, Manojkumar M, Bunker R, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL The CDK inhibitor CR8 acts as a molecular glue degrader depleting cyclin K. Nature. 2020; *These authors contributed equally.
BCL6 is a master transcription factor, when overexpressed in certain blood cells, can lead to the development of lymphoma. Turning off BCL6 in these cells could lead to the regression of disease. Recently a compound was published, which induces BCL6 degradation by unknown mechanism. To elucidate this mechanism, we fused BCL6 to a green fluorescent protein (GFP) and observed the appearance of distinct BCL6-GFP-containing foci within minutes of degrader treatment, followed by their subsequent degradation. To understand this phenomenon, we purified recombinant BCL6 protein and observed that, upon degrader treatment, BCL6 formed long coil shaped filaments in vitro. Finally, we identified SIAH1, an E3 ubiquitin ligase which is required for this drug-induced BCL6 degradation and toxicity. A manuscript describing this work is accepted for publication Słabicki M*, Yoon H*, Koeppel J*, Nitsch L, Burman SSR, 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. Small molecule-induced polymerization triggers degradation of BCL6. Nature.*These authors contributed equally
