A view to a kill: ligands for Bcl-2 family proteins.
Apoptosis is the essential process of programmed cell death that, in multicellular organisms, regulates development and maintains homeostasis. Defects in the apoptotic molecular machinery that result in either excessive or insufficient apoptosis are observed in a remarkably wide range of human disease, prompting intense interest in pro- and anti-apoptotic proteins as therapeutic targets. A number of recent reports have described the discovery of ligands for anti-apoptotic Bcl-2 family proteins by a variety of approaches, including computational, combinatorial and evolutionary strategies. Both the design of ligands and the exploration of their mechanisms of action have been greatly enhanced by recent high-resolution structure determinations of proteins from this family. Several of the newly discovered ligands promote apoptosis, and some do so even in the face of overexpressed anti-apoptotic Bcl-2 proteins. Ligands that overcome the protective effects associated with up-regulation of anti-apoptotic Bcl-2 proteins represent especially promising therapeutic leads.
Rutledge
Stacey E
SE
Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520-8107, USA.
Chin
Jason W
JW
Schepartz
Alanna
A
D017209:Apoptosis / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2