title: Small molecule inhibitors of Apaf-1-related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat de València, E-46100 Burjassot, València, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Malet
authors.forename: A G
authors.initials: AG
authors.lastname: Martín
authors.forename: M
authors.initials: M
authors.lastname: Orzáez
authors.forename: M J
authors.initials: MJ
authors.lastname: Vicent
authors.forename: I
authors.initials: I
authors.lastname: Masip
authors.forename: G
authors.initials: G
authors.lastname: Sanclimens
authors.forename: A
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: I
authors.initials: I
authors.lastname: Mingarro
authors.forename: A
authors.initials: A
authors.lastname: Messeguer
authors.forename: H O
authors.initials: HO
authors.lastname: Fearnhead
authors.forename: E
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D017209:Apoptosis; D053478:Apoptosomes / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D008928:Mitochondria / Q000502:physiology*; D034442:N-substituted Glycines / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D061945:Caspase Inhibitors; D008024:Ligands; D034442:N-substituted Glycines; D019151:Peptide Library; D011498:Protein Precursors; D011994:Recombinant Proteins; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9