Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity.
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.
Schimmer
Aaron D
AD
The Burnham Institute, La Jolla, CA 92037, USA.
Welsh
Kate
K
Pinilla
Clemencia
C
Wang
Zhiliang
Z
Krajewska
Maryla
M
Bonneau
Marie-Josee
MJ
Pedersen
Irene M
IM
Kitada
Shinichi
S
Scott
Fiona L
FL
Bailly-Maitre
Beatrice
B
Glinsky
Gennadi
G
Scudiero
Dominick
D
Sausville
Edward
E
Salvesen
Guy
G
Nefzi
Adel
A
Ostresh
John M
JM
Houghten
Richard A
RA
Reed
John C
JC
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
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