Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program

Malcolm A. Smith, John M. Maris, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, Christopher L. Morton, Jianrong Wu, Peter G. Smith, Jie Yu, Peter J. Houghton

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background: MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins. Procedures: MLN4924 was tested against the PPTP in vitro panel using 96-hour exposure time at concentrations ranging from 1.0nM to 10μM. It was tested in vivo at a dose of 100mg/kg [66mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily×5 days. Treatment duration was 3 weeks. Results: The median relative IC 50 for MLN4924 against the PPTP cell lines was 143nM, (range: 15-678nM) with that for the Ewing panel being significantly lower (31nM). 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 >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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)246-253
Number of pages8
JournalPediatric Blood and Cancer
Volume59
Issue number2
DOIs
StatePublished - Aug 1 2012

Keywords

  • Developmental therapeutics
  • MLN4924
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Smith, M. A., Maris, J. M., Gorlick, R., Kolb, E. A., Lock, R., Carol, H., Keir, S. T., Reynolds, C. P., Kang, M. H., Morton, C. L., Wu, J., Smith, P. G., Yu, J., & Houghton, P. J. (2012). Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 59(2), 246-253. https://doi.org/10.1002/pbc.23357