Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-08, Vol.47 (18), p.4417-4426
Main Authors: Oost, Thorsten K, Sun, Chaohong, Armstrong, Robert C, Al-Assaad, Ali-Samer, Betz, Stephen F, Deckwerth, Thomas L, Ding, Hong, Elmore, Steven W, Meadows, Robert P, Olejniczak, Edward T, Oleksijew, Andrew, Oltersdorf, Tilman, Rosenberg, Saul H, Shoemaker, Alexander R, Tomaselli, Kevin J, Zou, Hua, Fesik, Stephen W
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Baculovirus
Binding Sites
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Carrier Proteins - chemistry
Carrier Proteins - therapeutic use
Caspases - drug effects
Cell Division - drug effects
Cell Line, Tumor
General aspects
Humans
Intracellular Signaling Peptides and Proteins
Ligands
Medical sciences
Mice
Mitochondrial Proteins - chemistry
Mitochondrial Proteins - therapeutic use
Peptide Fragments - chemistry
Peptide Fragments - therapeutic use
Pharmacology. Drug treatments
Protein Structure, Tertiary
Proteins - antagonists & inhibitors
Structure-Activity Relationship
Transplantation, Heterologous
X-Linked Inhibitor of Apoptosis Protein
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Summary:Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm040037k