Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.

Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW
J Med Chem. 2004 47 (18): 4417-26

PMID: 15317454 · DOI:10.1021/jm040037k

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.

MeSH Terms (20)

Animals Antineoplastic Agents Apoptosis Binding Sites Breast Neoplasms Carrier Proteins Caspases Cell Division Cell Line, Tumor Humans Intracellular Signaling Peptides and Proteins Ligands Mice Mitochondrial Proteins Peptide Fragments Proteins Protein Structure, Tertiary Structure-Activity Relationship Transplantation, Heterologous X-Linked Inhibitor of Apoptosis Protein

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