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Closed Access item Small molecule inhibitors of Apaf-1-related caspase-3/-9 activation that control mitochondrial-dependent apoptosis

Authors:Malet Engra, Gema
Martín, A. G.
Orzáez, Mar
Vicent, María J.
Masip, Isabel
Sanclimens Pérez de Rozas, Gloria
Ferrer-Montiel, A.
Mingarro, Ismael
Messeguer Peypoch, Àngel
Fearnhead, H. O.
Pérez-Payá, Enrique
Keywords:Apoptosis, Apoptosome, Apaf-1, Caspasa-3, Caspasa-9, Combinatorial libraries inhibitor, Molecular recognition, Peptoid, Protein-protein interactions, Small molecule
Issue Date:2006
Publisher:Nature Publishing Group
Citation:Cell Death & Differentiation 13(9): 1523-1532 (2006)
Abstract:Apoptosis is a biological process relevant to human disease states that is strongly regulated through protein–protein complex formation. These complexes represent interesting points of chemical intervention for the development of molecules that could modulate cellular apoptosis. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated Apaf-1 (apoptotic protease-activating factor), dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators. In the present study we describe the identification of compounds that inhibit the apoptosome-mediated activation of procaspase-9 from the screening of a diversity-oriented chemical library. The active compounds rescued from the library were chemically optimised to obtain molecules that bind to both recombinant and human endogenous Apaf-1 in a cytochrome c-noncompetitive mechanism that inhibits the recruitment of procaspase-9 by the apoptosome. These newly identified Apaf-1 ligands decrease the apoptotic phenotype in mitochondrial-mediated models of cellular apoptosis.
Description:10 pages, 5 figures.-- PMID: 16341125 [PubMed].-- Available online Dec 9, 2005.
Supporting information available at: http://www.nature.com/cdd/journal/v13/n9/suppinfo/4401828s1.html?url=/cdd/journal/v13/n9/abs/4401828a.html
Publisher version (URL):http://dx.doi.org/10.1038/sj.cdd.4401828
URI:http://hdl.handle.net/10261/12153
ISSN:1350-9047 (Print)
1476-5403 (Online)
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