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bioRxiv · 10.1101/2022.01.24.477424

Hijacking Methyl Reader proteins for Nuclear-Specific Protein Degradation

Nalawansha, D. A.·Li, K.·Hines, J.·Crews, C. M.
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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 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.

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Nalawansha, D. A., Li, K., Hines, J., Crews, C. M.. 2022-01-27. Hijacking Methyl Reader proteins for Nuclear-Specific Protein Degradation. https://doi.org/10.1101/2022.01.24.477424

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