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

AuthorsMalet Engra, Gema; Martín, A. G.; Orzáez, Mar; Vicent, María J.; Masip, Isabel ; Sanclimens Pérez de Rozas, Gloria; Ferrer-Montiel, Antonio; Mingarro, Ismael; Messeguer Peypoch, Ángel ; Fearnhead, H. O.; Pérez-Payá, Enrique
Combinatorial libraries inhibitor
Molecular recognition
Protein-protein interactions
Small molecule
Issue Date2006
PublisherNature Publishing Group
CitationCell Death & Differentiation 13(9): 1523-1532 (2006)
AbstractApoptosis 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.
Description10 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
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