title: 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.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyalin
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
keywords: developmental therapeutics; mTOR inhibitor; preclinical testing