Open AccessHijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Author(s) -
Dhanusha A. Nalawansha,
Ke Li,
John Hines,
Craig M. Crews
Publication year - 2022
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.2c00874
Subject(s) - ubiquitin ligase , chemistry , protein degradation , dna ligase , ubiquitin , degradation (telecommunications) , cereblon , computational biology , toolbox , fkbp , proteasome , target protein , drug discovery , microbiology and biotechnology , mechanism (biology) , biochemistry , computer science , biology , enzyme , gene , telecommunications , philosophy , epistemology , programming language
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.