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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.<\/jats:p>","DOI":"10.1021\/jacs.3c06622","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T07:14:54Z","timestamp":1695885294000},"page":"21937-21944","source":"Crossref","is-referenced-by-count":74,"title":["Chemical Specification\nof E3 Ubiquitin Ligase Engagement\nby Cysteine-Reactive Chemistry"],"prefix":"10.1021","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8789-6150","authenticated-orcid":true,"given":"Roman C.","family":"Sarott","sequence":"first","affiliation":[{"name":"Stanford University , , , ,","place":["Stanford, California, United States, 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02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woong Sub","family":"Byun","sequence":"additional","affiliation":[{"name":"Stanford University , , , ,","place":["Stanford, California, United States, 94305"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Murtaza","family":"Hassan","sequence":"additional","affiliation":[{"name":"Stanford University , , , ,","place":["Stanford, California, United States, 94305"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Wachter","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute , , , ,","place":["Boston, Massachusetts, United States, 02215"]},{"name":"Harvard Medical School , , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"Harvard University , , , ,","place":["Boston, Massachusetts, United States, 02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward 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