Exploiting the Proteasome for Disease Treatment

Buel, Gwen R.; Lu, Xiuxiu; Walters, Kylie J.

doi:10.1002/9781119774198.ch4

Cited by 1 publication

(1 citation statement)

References 228 publications

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“…This is important as the linker length of other degraders has been shown to be important for inducing the proper confirmation for degradation. (38)(39)(40) To the other end of the linker, we installed a BRD4 ligand, JQ1, generating our first series of ByeTACs (TEC 2-9). This suite of degraders was assessed in cell lines reported to be reliant on Rpn-13 for survival in comparison to cell lines that are not as dependent on Rpn-13-mediated degradation.…”

Section: Resultsmentioning

confidence: 99%

ByeTAC: Bypassing an E3 Ligase for Targeted Protein Degradation

Ali,

Loy,

Trader

2024

Preprint

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Targeted protein degradation utilizing a bifunctional molecule to initiate ubiquitination and subsequent degradation by the 26S proteasome has been shown to be a powerful therapeutic intervention. Many bifunctional molecules, including covalent and non-covalent ligands to proteins of interest, have been developed. The traditional target protein degradation methodology targets the protein of interest in both healthy and diseased cell populations, and a therapeutic window is obtained based on the overexpression of the targeted protein. We report here a series of bifunctional degraders that do not rely on interacting with an E3 ligase, but rather a 26S proteasome subunit, which we have named ByeTACs: Bypassing E3 Targeting Chimeras. Rpn-13 is a non-essential ubiquitin receptor for the 26S proteasome. Cells under significant stress or require significant ubiquitin-dependent degradation of proteins for survival, incorporate Rpn-13 in the 26S to increase protein degradation rates. The targeted protein degraders reported here are bifunctional molecules that include a ligand to Rpn-13 and BRD4, the protein of interest we wish to degrade. We synthesized a suite of degraders with varying PEG chain lengths and showed that bifunctional molecules that incorporate a Rpn-13 binder (TCL1) and a BRD4 binder (JQ1) with a PEG linker of 3 or 4 units are the most effective to induce BRD4 degradation. We also demonstrate that our new targeted protein degraders are dependent upon proteasome activity and Rpn-13 expression levels. This establishes a new mechanism of action for our ByeTACs that can be employed for the targeted degradation of a wide variety of protein substrates.

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Section: Resultsmentioning

confidence: 99%