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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:p>Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome\u2019s three active sites (\u03b25) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31\/Fub1, that enters the proteasome\u2019s interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31\u2019s evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific \u03b22 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound\u2019s cell permeability and establishing \u03b22 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing \u03b25 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.<\/jats:p>","DOI":"10.1073\/pnas.2308417120","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T13:31:15Z","timestamp":1702474275000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31\/Fub1"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9090-0699","authenticated-orcid":false,"given":"Benjamin","family":"Velez","sequence":"first","affiliation":[{"name":"Department of Pathology, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1510-6612","authenticated-orcid":false,"given":"Aida","family":"Razi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Hubbard","sequence":"additional","affiliation":[{"name":"Mass General Brigham, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-8988","authenticated-orcid":false,"given":"Richard","family":"Walsh","sequence":"additional","affiliation":[{"name":"Harvard Cryo-Electron Microscopy Center for Structural Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-2630","authenticated-orcid":false,"given":"Shaun","family":"Rawson","sequence":"additional","affiliation":[{"name":"Harvard Cryo-Electron Microscopy Center for Structural Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geng","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Finley","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,12,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/386463a0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a033985"},{"key":"e_1_3_4_3_2","first-page":"596","article-title":"Bortezomib: A novel therapy approved for multiple myeloma","volume":"1","author":"Richardson P. 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