IAP antagonists: promising candidates for cancer therapy.

A promising strategy in cancer therapy aims to promote apoptosis in cancer cells. Targeting inhibitor of apoptosis proteins (IAPs) with small-molecule inhibitors has attracted increasing interest in triggering cancer cell death. It is considered to have great potential for cancer drug discovery because IAPs block apoptosis at the core of the apoptotic machinery and are aberrantly expressed in various tumors. This review focuses on the current development of small-molecule IAP antagonists for cancer therapy.

[1]  S. Hymowitz,et al.  Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists. , 2009, ACS chemical biology.

[2]  Emad S. Alnemri,et al.  A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis , 2001, Nature.

[3]  H. Steller,et al.  Regulation of apoptosis by XIAP ubiquitin-ligase activity. , 2008, Genes & development.

[4]  Xiaodong Wang,et al.  A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death , 2004, Science.

[5]  G. Salvesen,et al.  XIAP inhibits caspase‐3 and ‐7 using two binding sites: evolutionarily conserved mechanism of IAPs , 2005, The EMBO journal.

[6]  Dajun Yang,et al.  Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. , 2004 .

[7]  Shaomeng Wang,et al.  Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases. , 2008, Journal of medicinal chemistry.

[8]  M. Wigler,et al.  Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach , 2006, Cell.

[9]  R. Korneluk,et al.  The inhibitors of apoptosis (IAPs) as cancer targets , 2007, Apoptosis.

[10]  W. Sellers,et al.  A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. , 2007, Cancer research.

[11]  Shaomeng Wang,et al.  Design, synthesis, and characterization of new embelin derivatives as potent inhibitors of X-linked inhibitor of apoptosis protein. , 2006, Bioorganic & medicinal chemistry letters.

[12]  R. Lockshin,et al.  Cell death in health and disease , 2007, Journal of cellular and molecular medicine.

[13]  Chunying Du,et al.  Smac/DIABLO Selectively Reduces the Levels of c-IAP1 and c-IAP2 but Not That of XIAP and Livin in HeLa Cells* , 2004, Journal of Biological Chemistry.

[14]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[15]  Sheng Jiang,et al.  Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP. , 2007, Journal of the American Chemical Society.

[16]  Saul H Rosenberg,et al.  Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. , 2004, Journal of medicinal chemistry.

[17]  Su Qiu,et al.  Design of small-molecule peptidic and nonpeptidic Smac mimetics. , 2008, Accounts of chemical research.

[18]  R. J. Clem,et al.  An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif , 1993, Journal of virology.

[19]  Yigong Shi,et al.  Structure-activity based study of the Smac-binding pocket within the BIR3 domain of XIAP. , 2007, Bioorganic & medicinal chemistry.

[20]  Shaomeng Wang,et al.  Design and characterization of bivalent Smac-based peptides as antagonists of XIAP and development and validation of a fluorescence polarization assay for XIAP containing both BIR2 and BIR3 domains. , 2008, Analytical biochemistry.

[21]  Xuejun Jiang,et al.  A Dimeric Smac/Diablo Peptide Directly Relieves Caspase-3 Inhibition by XIAP , 2007, Journal of Biological Chemistry.

[22]  Vishva M. Dixit,et al.  IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis , 2007, Cell.

[23]  Geng Wu,et al.  Structural basis of IAP recognition by Smac/DIABLO , 2000, Nature.

[24]  W. Fairbrother,et al.  The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer , 2007, Clinical Cancer Research.

[25]  P. Schultz,et al.  Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction. , 2003, Chemistry & biology.

[26]  S. Srinivasula,et al.  IAPs: what's in a name? , 2008, Molecular cell.

[27]  C. Day,et al.  Assembling the building blocks: structure and function of inhibitor of apoptosis proteins , 2010, Cell Death and Differentiation.

[28]  Su Qiu,et al.  Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP). , 2008, Journal of medicinal chemistry.

[29]  M. Bertrand,et al.  cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. , 2008, Molecular cell.

[30]  Xiaodong Wang,et al.  Structural and biochemical basis of apoptotic activation by Smac/DIABLO , 2000, Nature.

[31]  Shaomeng Wang,et al.  Structure-based design of potent, conformationally constrained Smac mimetics. , 2004, Journal of the American Chemical Society.

[32]  W. Fairbrother,et al.  Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs. , 2006, ACS chemical biology.

[33]  Clemencia Pinilla,et al.  Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. , 2004, Cancer cell.

[34]  R. Lockshin,et al.  Programmed cell death—II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths , 1964 .

[35]  Shaomeng Wang,et al.  Design, synthesis, and evaluation of a potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase (Smac) mimetic. , 2006, Journal of medicinal chemistry.

[36]  S. Lowe,et al.  Intrinsic tumour suppression , 2004, Nature.

[37]  Seamus J. Martin,et al.  Smac/Diablo Antagonizes Ubiquitin Ligase Activity of Inhibitor of Apoptosis Proteins* , 2004, Journal of Biological Chemistry.

[38]  Chaohong Sun,et al.  Non-peptidic small molecule inhibitors of XIAP. , 2005, Bioorganic & medicinal chemistry letters.

[39]  Stephanie Birkey Reffey,et al.  Uncoupling of the Signaling and Caspase-inhibitory Properties of X-linked Inhibitor of Apoptosis* , 2004, Journal of Biological Chemistry.

[40]  Robert L Moritz,et al.  Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins , 2000, Cell.

[41]  N. Munshi,et al.  Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). , 2004, Blood.

[42]  Jiahuai Han,et al.  XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. , 2007, Molecular cell.

[43]  Yi Sun,et al.  A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells , 2005, Oncogene.

[44]  Shaomeng Wang,et al.  Interaction of a cyclic, bivalent smac mimetic with the x-linked inhibitor of apoptosis protein. , 2008, Biochemistry.

[45]  P. Goodford A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[46]  Bainan Wu,et al.  Fragment-based design of small molecule X-linked inhibitor of apoptosis protein inhibitors. , 2008, Journal of medicinal chemistry.

[47]  Stephen F. Betz,et al.  Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain , 2000, Nature.

[48]  Xiaodong Wang,et al.  Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition , 2000, Cell.

[49]  Shaomeng Wang,et al.  SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. , 2008, Cancer research.

[50]  Carlo Scolastico,et al.  Targeting the X-linked inhibitor of apoptosis protein through 4-substituted azabicyclo[5.3.0]alkane smac mimetics. Structure, activity, and recognition principles. , 2008, Journal of molecular biology.

[51]  John Calvin Reed,et al.  Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. , 2005, Cancer research.

[52]  S. Baird,et al.  IAP-targeted therapies for cancer , 2008, Oncogene.

[53]  Yigong Shi,et al.  Molecular mechanisms of caspase regulation during apoptosis , 2004, Nature Reviews Molecular Cell Biology.

[54]  David L. Vaux,et al.  IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis , 2007, Cell.

[55]  M. Bolognesi,et al.  Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. , 2009, Biochemical and biophysical research communications.

[56]  G. Mclendon,et al.  Biochemical basis for enhanced binding of peptide dimers to X-linked inhibitor of apoptosis protein. , 2007, Biochemistry.

[57]  R. Rich,et al.  Requirement of Both the Second and Third BIR Domains for the Relief of X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Caspase Inhibition by Smac* , 2003, Journal of Biological Chemistry.

[58]  Shaomeng Wang,et al.  Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site. , 2004, Journal of medicinal chemistry.