Discovery of a tetrahydroisoquinoline-based hydroxamic acid derivative (ZYJ-34c) as histone deacetylase inhibitor with potent oral antitumor activities

J Med Chem. 2011 Aug 11;54(15):5532-9. doi: 10.1021/jm200577a. Epub 2011 Jul 11.

Abstract

Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytostatic Agents / pharmacology
  • Female
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use*
  • Isoquinolines / chemical synthesis
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use*
  • Mice
  • Vorinostat
  • Xenograft Model Antitumor Assays

Substances

  • 2-(2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
  • Cytostatic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Isoquinolines
  • Vorinostat