{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:04:19Z","timestamp":1776794659840,"version":"3.51.2"},"reference-count":40,"publisher":"Portland Press Ltd.","issue":"2","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.<\/jats:p>","DOI":"10.1042\/bsr20212721","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T04:26:46Z","timestamp":1643344006000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degeneration\n                    <i>in vivo<\/i>"],"prefix":"10.1042","volume":"42","author":[{"given":"Vasudha","family":"Tandon","sequence":"first","affiliation":[{"name":"Department of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruturajsinh\u00a0M.","family":"Vala","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert\u00a0L.","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitendra\u00a0M.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael\u00a0C.","family":"Pirrung","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Riverside, CA 92521, U.S.A."},{"name":"Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2043-2989","authenticated-orcid":false,"given":"Sourav","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"2022021108491555100_B1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1083\/jcb.201210077","article-title":"Development of proteasome inhibitors as research tools and cancer drugs","volume":"199","author":"Goldberg","year":"2012","journal-title":"J. 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