Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain

J Med Chem. 2013 Oct 24;56(20):7788-803. doi: 10.1021/jm400732v. Epub 2013 Oct 7.

Abstract

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / chemical synthesis
  • Alanine / pharmacokinetics
  • Alanine / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / pharmacokinetics
  • Benzodiazepinones / pharmacology
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Female
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / chemistry
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mice
  • Mice, Nude
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Protein Structure, Tertiary
  • Ubiquitin-Protein Ligases
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / chemistry
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Benzodiazepinones
  • Heterocyclic Compounds
  • Inhibitor of Apoptosis Proteins
  • N-(5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2-(methylamino)propanamide
  • X-Linked Inhibitor of Apoptosis Protein
  • BIRC2 protein, human
  • Ubiquitin-Protein Ligases
  • Caspase 3
  • Caspase 7
  • Alanine

Associated data

  • PDB/4KJU