title: Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program.
abstract: AT13387, a non-geldanamycin inhibitor of heat-shock protein 90 (HSP90), was tested against the PPTP in vitro panel (1.0 nM to 10 µM) and against the PPTP in vivo panels (40 or 60 mg/kg) administered orally twice weekly. In vitro AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect. In vivo AT13387 induced significant differences in EFS distribution compared to controls in 17% evaluable solid tumor xenografts, but in none of the ALL xenografts. No objective tumor responses were observed. In vivo AT13387 demonstrated only modest single agent activity.
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6450, USA. min.kang@ttuhsc.edu
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Denise
authors.initials: D
authors.lastname: Alexander
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Amy
authors.initials: A
authors.lastname: Wozniak
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone