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  Chemical specification of E3 ubiquitin ligase engagement by cysteine-reactive chemistry

Sarott, R. C., You, I., Li, Y.-D., Toenjes, S. T., Donovan, K. A., Seo, P., et al. (2023). Chemical specification of E3 ubiquitin ligase engagement by cysteine-reactive chemistry. Journal of the American Chemical Society, 145(40), 21937-21944. doi:10.1021/jacs.3c06622.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000F-F371-F Version Permalink: https://hdl.handle.net/21.11116/0000-000F-F372-E
Genre: Journal Article

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 Creators:
Sarott, Roman C.1, Author           
You, Inchul, Author
Li, Yen-Der, Author
Toenjes, Sean T., Author
Donovan, Katherine A., Author
Seo, Pooreum, Author
Ordonez, Martha, Author
Byun, Woong Sub, Author
Hassan, Muhammad Murtaza, Author
Wachter, Franziska, Author
Chouchani, Edward T., Author
Słabicki, Mikołaj, Author
Fischer, Eric S., Author
Ebert, Benjamin L., Author
Hinshaw, Stephen M., Author
Gray, Nathanael S., Author
Affiliations:
1Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society, ou_2364732              

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 Abstract: Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

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Language(s): eng - English
 Dates: 2023-06-222024-09-282023-10-11
 Publication Status: Issued
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: URI: https://pubmed.ncbi.nlm.nih.gov/37767920/
DOI: 10.1021/jacs.3c06622
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Title: Journal of the American Chemical Society
  Other : JACS
  Abbreviation : J. Am. Chem. Soc.
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 145 (40) Sequence Number: - Start / End Page: 21937 - 21944 Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870