A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment

J Med Chem. 2011 Apr 28;54(8):2714-26. doi: 10.1021/jm101505d. Epub 2011 Mar 28.


We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Area Under Curve
  • Azocines / pharmacokinetics
  • Azocines / pharmacology*
  • Azocines / therapeutic use
  • Benzhydryl Compounds / pharmacokinetics
  • Benzhydryl Compounds / pharmacology*
  • Benzhydryl Compounds / therapeutic use
  • Biological Availability
  • Cell Line, Tumor
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Models, Molecular
  • Neoplasms / drug therapy*


  • Antineoplastic Agents
  • Azocines
  • Benzhydryl Compounds
  • Inhibitor of Apoptosis Proteins
  • N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide