Download MendeleyDiscovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer.
Oost, T.K., Sun, C., Armstrong, R.C., Al-Assaad, A.S., Betz, S.F., Deckwerth, T.L., Ding, H., Elmore, S.W., Meadows, R.P., Olejniczak, E.T., Oleksijew, A., Oltersdorf, T., Rosenberg, S.H., Shoemaker, A.R., Tomaselli, K.J., Zou, H., Fesik, S.W.(2004) J Med Chem 47: 4417-4426
- PubMed: 15317454
- DOI: https://doi.org/10.1021/jm040037k
- Primary Citation of Related Structures:
1TFQ, 1TFT - PubMed Abstract:
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.
Organizational Affiliation:
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
