{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:20:45Z","timestamp":1791217245136,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,10,19]],"date-time":"2011-10-19T00:00:00Z","timestamp":1318982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["NO1-CM-42216"],"award-info":[{"award-number":["NO1-CM-42216"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["CA21765"],"award-info":[{"award-number":["CA21765"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["CA108786"],"award-info":[{"award-number":["CA108786"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>MLN4924 is an investigational first\u2010in\u2010class small molecule inhibitor of NEDD8\u2010activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin\u2010proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedures<\/jats:title><jats:p>MLN4924 was tested against the PPTP in vitro panel using 96\u2010hour exposure time at concentrations ranging from 1.0\u2009nM to 10\u2009\u00b5M. It was tested in vivo at a dose of 100\u2009mg\/kg [66\u2009mg\/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily\u2009\u00d7\u20095 days. Treatment duration was 3 weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The median relative IC<jats:sub>50<\/jats:sub> for MLN4924 against the PPTP cell lines was 143\u2009nM, (range: 15\u2013678\u2009nM) with that for the Ewing panel being significantly lower (31\u2009nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T\/C values &gt;2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilm's tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T\/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts. Pediatr Blood Cancer 2012;59:246\u2013253. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.23357","type":"journal-article","created":{"date-parts":[[2011,10,19]],"date-time":"2011-10-19T12:09:04Z","timestamp":1319026144000},"page":"246-253","source":"Crossref","is-referenced-by-count":31,"title":["Initial testing of the investigational NEDD8\u2010activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program"],"prefix":"10.1002","volume":"59","author":[{"given":"Malcolm A.","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Maris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gorlick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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