642090-91-3Relevant academic research and scientific papers
Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer
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.
, p. 4417 - 4426 (2007/10/03)
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.
PEPTIDE INHIBITORS OF SMAC PROTEIN BINDING TO INHIBITOR OF APOPTOSIS PROTEINS (IAP)
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Page 16, (2010/02/06)
The present disclosure relates to XIAP inhibitor compounds of the formula I (I) wherein the substituents are as described in the specification. The inventive compounds are useful as therapeutic agents for the treatment of proliferative disorders, includin
