Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program

Pediatr Blood Cancer. 2012 Jul 15;59(1):185-8. doi: 10.1002/pbc.23154. Epub 2011 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacokinetics*
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Female
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Isoindoles / pharmacokinetics*
  • Isoindoles / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, SCID
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • Benzamides
  • HSP90 Heat-Shock Proteins
  • Isoindoles
  • (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone