title: Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity.
abstract: Apoptosis resistance commonly occurs in cancers, preventing activation of Caspase family cell death proteases. XIAP is an endogenous inhibitor of Caspases overexpressed in many cancers. We developed an enzyme derepression assay, based on overcoming XIAP-mediated suppression of Caspase-3, and screened mixture-based combinatorial chemical libraries for compounds that reversed XIAP-mediated inhibition of Caspase-3, identifying a class of polyphenylureas with XIAP-inhibitory activity. These compounds, but not inactive structural analogs, stimulated increases in Caspase activity, directly induced apoptosis of many types of tumor cell lines in culture, and sensitized cancer cells to chemotherapeutic drugs. Active compounds also suppressed growth of established tumors in xenograft models in mice, while displaying little toxicity to normal tissues. These findings validate IAPs as targets for cancer drug discovery.
authors.affiliation: The Burnham Institute, La Jolla, CA 92037, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Marie-Josee
authors.initials: MJ
authors.lastname: Bonneau
authors.forename: Irene M
authors.initials: IM
authors.lastname: Pedersen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Scott
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: Gennadi
authors.initials: G
authors.lastname: Glinsky
authors.forename: Dominick
authors.initials: D
authors.lastname: Scudiero
authors.forename: Edward
authors.initials: E
authors.lastname: Sausville
authors.forename: Guy
authors.initials: G
authors.lastname: Salvesen
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: John M
authors.initials: JM
authors.lastname: Ostresh
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014183:Transplantation, Heterologous / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011506:Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases