Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation.

ABSTRACT: 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 ap

SUBMITTER: Nalawansha DA 

PROVIDER: S-EPMC10331457 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature