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

17 Citations (Scopus)

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 2012

Fingerprint

Enzyme Inhibitors
Heterografts
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Ubiquitin
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulphamate
Multiprotein Complexes
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Enzymes
Glioblastoma
Neuroblastoma
Cell Line
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine
Growth

Keywords

  • Developmental therapeutics
  • MLN4924
  • Preclinical testing

ASJC Scopus subject areas

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

Cite this

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. Pediatric Blood and Cancer, 59(2), 246-253. https://doi.org/10.1002/pbc.23357

Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. / Smith, Malcolm A.; Maris, John M.; Gorlick, Richard; Kolb, E. Anders; Lock, Richard; Carol, Hernan; Keir, Stephen T.; Reynolds, C. Patrick; Kang, Min H.; Morton, Christopher L.; Wu, Jianrong; Smith, Peter G.; Yu, Jie; Houghton, Peter J.

In: Pediatric Blood and Cancer, Vol. 59, No. 2, 08.2012, p. 246-253.

Research output: Contribution to journalArticle

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 2012, 'Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 59, no. 2, pp. 246-253. https://doi.org/10.1002/pbc.23357
Smith, Malcolm A. ; Maris, John M. ; Gorlick, Richard ; Kolb, E. Anders ; Lock, Richard ; Carol, Hernan ; Keir, Stephen T. ; Reynolds, C. Patrick ; Kang, Min H. ; Morton, Christopher L. ; Wu, Jianrong ; Smith, Peter G. ; Yu, Jie ; Houghton, Peter J. / Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2012 ; Vol. 59, No. 2. pp. 246-253.
@article{65e403936f2e435882782669c88aca20,
title = "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 1.0nM 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.",
keywords = "Developmental therapeutics, MLN4924, Preclinical testing",
author = "Smith, {Malcolm A.} and Maris, {John M.} and Richard Gorlick and Kolb, {E. Anders} and Richard Lock and Hernan Carol and Keir, {Stephen T.} and Reynolds, {C. Patrick} and Kang, {Min H.} and Morton, {Christopher L.} and Jianrong Wu and Smith, {Peter G.} and Jie Yu and Houghton, {Peter J.}",
year = "2012",
month = "8",
doi = "10.1002/pbc.23357",
language = "English (US)",
volume = "59",
pages = "246--253",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program

AU - Smith, Malcolm A.

AU - Maris, John M.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Lock, Richard

AU - Carol, Hernan

AU - Keir, Stephen T.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Morton, Christopher L.

AU - Wu, Jianrong

AU - Smith, Peter G.

AU - Yu, Jie

AU - Houghton, Peter J.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

KW - Developmental therapeutics

KW - MLN4924

KW - Preclinical testing

UR - http://www.scopus.com/inward/record.url?scp=84862269352&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862269352&partnerID=8YFLogxK

U2 - 10.1002/pbc.23357

DO - 10.1002/pbc.23357

M3 - Article

VL - 59

SP - 246

EP - 253

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 2

ER -