Proteolysis-targeting chimeras (PROTACs) are small molecules that specifically link E3 ubiquitin ligases to proteins of interest to mediate targeted ubiquitination and degradation. PROTACs are advantageous since they can target undruggable proteins with multiple domains, particularly those with smooth surfaces that lack a common binding domain for small-molecule inhibitors (SMIs). This review provides an overview of PROTAC technology and third-generation PROTAC development. We focused on designing and executing the most recent clinical trials involving PROTACs in cancer therapy. Additionally, we summarized novel findings regarding the mechanisms and signaling pathways involved in cancer development, such as the scaffolding function of certain proteins ignored by traditional SMIs and several recognized oncoproteins that participate in novel signaling pathways. We also discussed strategies for enhancing PROTAC antitumor activity and specificity.
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RNA G-quadruplexes (rG4s) are non-canonical secondary nucleic acid structures found in the transcriptome. They play crucial roles in gene regulation by interacting with G4-binding proteins (G4BPs) in cells. rG4-G4BP complexes have been associated with human diseases, making them important targets for drug development.
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Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted protein degradation (TPD) offers an alternative approach by harnessing cellular degradation pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD by identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating protein degradation through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms.
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