RT Journal Article
SR Electronic
T1 Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.24.477424
DO 10.1101/2022.01.24.477424
A1 Nalawansha, Dhanusha A.
A1 Li, Ke
A1 Hines, John
A1 Crews, Craig M.
YR 2022
UL http://biorxiv.org/content/early/2022/01/27/2022.01.24.477424.1.abstract
AB 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 Cul4DCAF5 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.Competing Interest StatementC.M.C. is a shareholder in Arvinas, Inc. and in Halda, LLC, for which he consults and receives laboratory research support.