Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists

Bioorg Med Chem Lett. 2014 Nov 1;24(21):5022-9. doi: 10.1016/j.bmcl.2014.09.022. Epub 2014 Sep 16.

Abstract

Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.

Keywords: A875 melanoma; Bivalent; IAP; Terahydroisoquinoline.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Binding Sites
  • Drug Discovery*
  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Melanoma / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Pancreatic Neoplasms / drug therapy*
  • Tetrahydroisoquinolines / chemistry*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Inhibitor of Apoptosis Proteins
  • Tetrahydroisoquinolines