5- t Bu-Thalidomide Is a Selective Molecular Glue Degrader of the Transcription Factor FLT3 Interacting Zinc Finger 1 (FIZ1)

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Abstract Cys2-His2 (C2H2) zinc finger (ZF)-containing proteins are the largest family of human DNA-binding transcription factors (TFs), a class of proteins that has long been considered undruggable. Significant progress has recently been made in the development of immunomodulatory imide drugs (IMiDs) that induce the degradation of proteins that possess the G-loop CXXCG degron, including these transcription factors. Despite these advances, the identification of IMiD-based molecular glues that selectively induce the degradation of a single protein, and the rational design of such compounds, remains challenging. Here we report the serendipitous discovery that 5-tBu-thalidomide (tBu-Thal, 5) potently and selectively induces proteasomal degradation of a single C2H2 ZF-containing TF, FLT3 interacting zinc finger 1 (FIZ1), in six cell lines. While FIZ1 contains 11 C2H2 ZFs, six of which contain the G-loop CXXCG degron necessary for IMiD-induced degradation, we demonstrate that this degradation is mediated exclusively by ZF8. Computational modeling of the CRL4CRBN-IMiD-FIZ1 complex enabled rationalization of why tBu-Thal (5) selectively engages with ZF8, and hints at a strategy for more rational design of selective IMiD-based degraders. tBu-Thal (5) was employed in ChIP-seq studies to identify a motif matching the CRX binding site, consistent with prior reports. We also identified enriched motifs resembling binding sites of the transcription factors ZBTB32 and ARID3a, which have not previously been associated with FIZ1. IP-MS studies indicated that FIZ1 associates with C1QBP and YBX1. C1QBP is involved in DNA damage repair, suggesting a role for FIZ1 in this process. These data show that tBu-Thal (5) is a powerful molecular tool to selectively dissect the role of FIZ1 in complex biological settings.

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