Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program

Pediatr Blood Cancer. 2014 Aug;61(8):1486-9. doi: 10.1002/pbc.24989. Epub 2014 Feb 20.

Abstract

MLN0128 is an investigational small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR. MLN0128 was tested against the in vitro panel at concentrations ranging from 0.1 nM to 1 μM and against the PPTP in vivo panels at a dose of 1 mg/kg administered orally daily × 28. In vitro the median relative IC(50) concentration was 19 nM. In vivo MLN0128 induced significant differences in EFS in 24/31 (77%) solid tumor models, but 0/7 ALL xenografts. The modest activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported for another TOR kinase inhibitor.

Keywords: developmental therapeutics; mTOR inhibitor; preclinical testing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoxazoles / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Experimental* / drug therapy
  • Neoplasms, Experimental* / enzymology
  • Neoplasms, Experimental* / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • Benzoxazoles
  • INK128
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • MTOR protein, human
  • TOR Serine-Threonine Kinases