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

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 1.0 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.

• Authors: 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
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 59 Issue 2 Pg. 246-53 (Aug 2012) ISSN: 1545-5017 [Electronic] United States
• PMID: 22012946 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Cyclopentanes
• NEDD8 Protein
• NEDD8 protein, human
• Nedd8 protein, mouse
• Pyrimidines
• Ubiquitins
• pevonedistat

Topics

• Animals
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Child
• Cyclopentanes (pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, SCID
• NEDD8 Protein
• Neuroblastoma (drug therapy, metabolism, pathology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)
• Pyrimidines (pharmacology)
• Sarcoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Ubiquitins (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays