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Zinc finger proteins (ZFPs) constitute one of the most abundant protein families in eukaryotes, defined by the presence of small, functional motifs stabilized by the coordination of zinc ions (UniProt, 2023). These proteins primarily act as transcription factors that bind specific DNA sequences to control the expression of genes involved in cell growth, differentiation, and development (PubMed, 2021). Beyond DNA binding, ZFPs are also involved in RNA metabolism, protein-protein interactions, and the regulation of apoptosis (NIH, 2022). Dysregulation or mutation of ZFPs is frequently observed in various diseases, particularly in oncology where they can act as either oncogenes or tumor suppressors (Nature Reviews Cancer, 2020). For instance, the Wilms tumor 1 (WT1) protein is a well-characterized ZFP that plays a critical role in leukemogenesis and solid tumors (PubMed, 2019). Therapeutic strategies targeting ZFPs include the use of molecular glues like lenalidomide to induce the degradation of Ikaros family proteins (IKZF1/3) via the CRBN E3 ligase (Science, 2019). Additionally, engineered zinc finger nucleases (ZFNs) have been developed for therapeutic gene editing to treat genetic disorders and HIV (Nature Biotechnology, 2021). Despite their potential, targeting ZFPs remains challenging due to the high structural homology between family members, which can lead to off-target effects (Cell, 2022).
Molecular glue-induced degradation, competitive inhibition of DNA binding, and site-specific genomic cleavage.
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