title: Small molecule inhibitor of apoptosis proteins antagonists: a patent review.
abstract: BACKGROUND
  The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.
  
  
  METHODS
  This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists.
  
  
  CONCLUSIONS
  In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space - for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles - tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.
authors.affiliation: AstraZeneca, Medicinal Chemistry, Oncology iMed , 35 Gatehouse Drive, Waltham, MA 02451 , USA +1 781 839 4145 ; alexander.hird@astrazeneca.com.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Hird
authors.forename: Brian M
authors.initials: BM
authors.lastname: Aquila
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Vasbinder
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D040761:Biomimetic Materials / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000737:chemistry; D010330:Patents as Topic; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide
keywords: BIR2 selective; Smac mimetics; apoptosis; bivalent Smac mimetics; inhibitor of apoptosis protein antagonists; inhibitor of apoptosis proteins; monovalent Smac mimetics