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

Publication ,  Journal Article
Smith, MA; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Morton, CL; Wu, J; Smith, PG; Yu, J; Houghton, PJ
Published in: Pediatr Blood Cancer
August 2012

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 1.0 nM to 10 µM. It was tested in vivo at a dose of 100 mg/kg [66 mg/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 143 nM, (range: 15-678 nM) with that for the Ewing panel being significantly lower (31 nM). 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.

Duke Scholars

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

August 2012

Volume

59

Issue

2

Start / End Page

246 / 253

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitins
  • Tumor Cells, Cultured
  • Sarcoma
  • Pyrimidines
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Oncology & Carcinogenesis
  • Neuroblastoma
  • NEDD8 Protein
  • Mice, SCID
 

Citation

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Smith, M. A., Maris, J. M., Gorlick, R., Kolb, E. A., Lock, R., Carol, H., … Houghton, P. J. (2012). Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer, 59(2), 246–253. https://doi.org/10.1002/pbc.23357
Smith, Malcolm A., John M. Maris, Richard Gorlick, E Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, et al. “Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program.Pediatr Blood Cancer 59, no. 2 (August 2012): 246–53. https://doi.org/10.1002/pbc.23357.
Smith MA, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, et al. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Aug;59(2):246–53.
Smith, Malcolm A., et al. “Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 59, no. 2, Aug. 2012, pp. 246–53. Pubmed, doi:10.1002/pbc.23357.
Smith MA, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Reynolds CP, Kang MH, Morton CL, Wu J, Smith PG, Yu J, Houghton PJ. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Aug;59(2):246–253.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

August 2012

Volume

59

Issue

2

Start / End Page

246 / 253

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitins
  • Tumor Cells, Cultured
  • Sarcoma
  • Pyrimidines
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Oncology & Carcinogenesis
  • Neuroblastoma
  • NEDD8 Protein
  • Mice, SCID