Targeting apoptosis via chemical design: inhibition of bid-induced cell death by small organic molecules

Chem Biol. 2004 Aug;11(8):1107-17. doi: 10.1016/j.chembiol.2004.05.022.


Bid is a key member of the Bcl-2 family proteins involved in the control of the apoptotic cascade in cells, leading to cell death. Uncontrolled cell death is associated with several human pathologies, such as neurodegenerative diseases and ischemic injuries. Therefore, Bid represents a potential yet unexplored and challenging target for strategies aimed at the development of therapeutic agents. Here we show that a multidisciplinary NMR-based approach that we named SAR by ILOEs (structure activity relationships by interligand nuclear Overhauser effect) allowed us to rationally design a series of 4-phenylsulfanyl-phenylamine derivatives that are capable of occupying a deep hydrophobic crevice on the surface of Bid. These compounds represent the first antiapoptotic small molecules targeting a Bcl-2 protein as shown by their ability to inhibit tBid-induced SMAC release, caspase-3 activation, and cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • BH3 Interacting Domain Death Agonist Protein
  • Binding Sites
  • Biological Assay
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Line
  • Drug Design*
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Pharmaceutical Preparations / chemical synthesis
  • Pharmaceutical Preparations / chemistry
  • Protein Structure, Tertiary


  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Ligands
  • Pharmaceutical Preparations