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

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.

• Authors: Min H Kang, C Patrick Reynolds, John M Maris, Richard Gorlick, E Anders Kolb, Richard Lock, Hernan Carol, Stephen T Keir, Jianrong Wu, Dmitry Lyalin, Raushan T Kurmasheva, Peter J Houghton, Malcolm A Smith
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 8 Pg. 1486-9 (Aug 2014) ISSN: 1545-5017 [Electronic] United States
• PMID: 24623675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

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

Topics

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