PDBsum entry 1tft

Apoptosis

PDB id: 1tft

Contents

Protein chain

117 a.a.

Ligands

997

Metals

_ZN

References listed in PDB file

Key reference

• Title: Discovery of potent antagonists of the antiapoptotic protein xiap for the treatment of cancer.
• Authors: T.K.Oost, C.Sun, R.C.Armstrong, A.S.Al-Assaad, S.F.Betz, T.L.Deckwerth, H.Ding, S.W.Elmore, R.P.Meadows, E.T.Olejniczak, A.Oleksijew, T.Oltersdorf, S.H.Rosenberg, A.R.Shoemaker, K.J.Tomaselli, H.Zou, S.W.Fesik.
• Ref.: J Med Chem, 2004, 47, 4417-4426. [DOI no: 10.1021/jm040037k]
• PubMed id: 15317454

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.