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

Abstract

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.

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@article{Becattini2004TargetingAV, title={Targeting apoptosis via chemical design: inhibition of bid-induced cell death by small organic molecules.}, author={Barbara Becattini and Sina Sareth and Dayong Zhai and Kevin J Crowell and Marilisa Leone and John C. Reed and Maurizio Pellecchia}, journal={Chemistry & biology}, year={2004}, volume={11 8}, pages={1107-17} }