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Temporal and Spatial Characterization of CUL3-driven Targeted Degradation of BET family, BRD Proteins by the Macrocycle-based Degrader BTR2004. | LitMetric

AI Article Synopsis

  • Targeted protein degradation (TPD) uses the body's natural protein breakdown system to selectively degrade specific proteins, which could be a new approach for therapies.
  • Researchers created a synthetic macrocycle ligand, KLHL20, which helps target CUL3 E3 ligase, leading to the development of PROTAC BTR2004 that effectively degrades certain BET family proteins.
  • The study provides detailed insights into how BTR2004 works, including the speed of protein degradation, its effectiveness inside cells, and how it interacts with cell structures, aiding future TPD research and PROTAC design.

Article Abstract

Targeted protein degradation (TPD) is a promising new therapeutic modality that leverages the endogenous cellular protein degradation machinery of the ubiquitin-proteasome system (UPS) to degrade selected proteins. Recently, we developed a synthetic macrocycle ligand to recruit CUL3 E3 ligase for TPD. Using this KLHL20 ligand, we constructed the PROTAC BTR2004, which demonstrated potent degradation of BET family proteins BRD 2, 3, and 4. As the TPD field expands, it is important to understand the cellular and biochemical properties of all utilized E3 ligases. Herein we report the temporal and spatial processes of BTR2004-facilitated BET family protein degradation by KLHL20: The target protein degradation kinetics, BTR2004 intracellular activity half-life, and the onset of BTR2004 cell permeabilization. Employing proximity ligation and confocal microscopy techniques, we also illustrate the subcellular location of the ternary complex assembly upon BTR2004 treatment. These characterizations provide further insight into the processes that govern TPD and features that could be incorporated when designing future PROTAC molecules.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643031PMC
http://dx.doi.org/10.1101/2024.12.07.627262DOI Listing

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