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Ken and Donna Coit Endowed Chair fund in Drug Discovery"},{"name":"NIH","award":["AG092462-01"],"award-info":[{"award-number":["AG092462-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>UBA5 is the E1 enzyme that initiates UFMylation, a ubiquitin-like modification implicated in proteostasis, neurodegeneration, and cancer. Here, we report a chemical biology approach to interrogate UBA5 function through small-molecule inhibition. We developed a robust high-throughput screening assay based on AMP-GloTM and screened a library of blood\u2013brain barrier-permeable compounds, identifying five inhibitors spanning three distinct scaffolds with low-micromolar potency. Orthogonal biochemical and gel-based assays confirmed that these compounds directly inhibit UBA5-mediated UFM1 activation and conjugation, with selectivity over other E1 enzymes, including UBA1. In cells, these compounds suppressed endogenous UFMylation without significantly affecting global polyubiquitination, supporting pathway and target engagement. Together, these studies establish UBA5 as a tractable enzymatic target and provide first-in-class chemical tools to probe UFMylation. Given the emerging role of UFMylation in disease, these inhibitors offer a foundation for developing therapeutics targeting proteostasis pathways.<\/jats:p>","DOI":"10.1021\/acschembio.6c00369","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T19:01:54Z","timestamp":1786993314000},"page":"2200-2215","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and Characterization of Inhibitors of Ubiquitin-Like Modifier Activating Enzyme 5 (UBA5): Targeting the UFMylation Pathway in Cancer and Neurodegenerative Diseases"],"prefix":"10.1021","volume":"21","author":[{"given":"Vigyasa","family":"Singh","sequence":"first","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9318-9145","authenticated-orcid":true,"given":"Yuansong","family":"Wan","sequence":"additional","affiliation":[{"name":"Brain and Mind Research Institute, Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhisong","family":"Gao","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahsin Reaz","family":"Ahmed","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Brain and Mind Research Institute, Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subodh","family":"Kumar Samrat","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Li","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8916-5677","authenticated-orcid":true,"given":"Subhash","family":"Sinha","sequence":"additional","affiliation":[{"name":"Brain and Mind Research Institute, Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gan","sequence":"additional","affiliation":[{"name":"Brain and Mind Research Institute, Weill Cornell Medicine , , , ,","place":["New York, New York, United States, 10021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8684-5308","authenticated-orcid":true,"given":"Hongmin","family":"Li","sequence":"additional","affiliation":[{"name":"R Ken Coit College of Pharmacy , , 1703 E Mabel St , , ,","place":["Tucson, Arizona, United States, 85721-0207"]},{"name":"The University of Arizona , , , ,","place":["Tucson, Arizona, United States, 85721"]},{"name":"The University of Arizona , , , ,","place":["Tucson, Arizona, United States, 85721"]},{"name":"The University of Arizona , , , ,","place":["Tucson, Arizona, United States, 85721"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"2026101511062650300_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2024.108680","article-title":"UFMylation: An integral post-translational modification for the regulation of proteostasis and cellular functions","volume":"260","author":"Wang","year":"2024","journal-title":"Pharmacol. 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