Abstract PL02-03: The zinc-finger degrome

The small molecule drugs thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3) by mediating their interaction with Cereblon (CRBN), the substrate receptor of the CRL4CRBN ubiquitin ligase. Here we screened the human Cys2-His2 (C2H2) zinc finger (ZF) proteome for degradation by CRL4CRBN in the presence of thalidomide analogues, identifying 11 ZF targets. Structural and functional characterization of the C2H2 zinc finger degron demonstrates how diverse ZF domains bind the drug-CRBN interface. Computational ZF docking, in conjunction with biochemical analysis, predicts that at least 50 zinc-fingers bind the drug-CRBN complex in vitro, a larger number than previously anticipated. These results provide strategies to degrade other zinc finger transcription factors. Citation Format: Quinlan L. Sievers, Georg Petzold, Richard D. Bunker, Aline Renneville, Brian Liddicoat, Wassim Abdulrahman, Tarjei Mikkelsen, Benjamin L. Ebert, Nicolas H. Thoma. The zinc-finger degrome [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL02-03. doi:10.1158/1535-7163.TARG-19-PL02-03