4.8 Article

Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 12, Pages 5594-5605

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c00874

Keywords

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Funding

  1. NIH [R35CA197589, R01CA238570]
  2. American Cancer Research Professorship

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This study introduces a novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex, demonstrating nuclear-specific degradation of FKBP12 and BRD2.
Targeted protein degradation (TPD) by PROTACs is a promising strategy to control disease-causing protein levels within the cell. While TPD is emerging as an innovative drug discovery paradigm, there are currently only a limited number of E3 ligase:ligand pairs that are employed to induce protein degradation. Herein, we report a novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex. L3MBTL3 is a methyl-lysine reader protein that binds to the Cul4(DCAF5) E3 ligase complex and targets methylated proteins for proteasomal degradation. By co-opting this natural mechanism, we report the design and biological evaluation of L3MBTL3-recruiting PROTACs and demonstrate nuclear-specific degradation of FKBP12 and BRD2. We envision this as a generalizable approach to utilize other reader protein-associated E3 ligase complexes in PROTAC design to expand the E3 ligase toolbox and explore the full potential of TPD.

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