Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases.

A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.

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

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

[3]  Yahong Lin,et al.  A JNK-Dependent Pathway Is Required for TNFα-Induced Apoptosis , 2003, Cell.

[4]  S. Fulda.  Inhibitor of apoptosis proteins as targets for anticancer therapy , 2007, Expert review of anticancer therapy.

[5]  G. Salvesen,et al.  Apoptosis: IAP proteins: blocking the road to death's door , 2002, Nature Reviews Molecular Cell Biology.

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

[7]  S. Srinivasula,et al.  Mechanism of XIAP-mediated inhibition of caspase-9. , 2003, Molecular cell.

[8]  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.

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

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

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

[12]  Shaomeng Wang,et al.  Design and synthesis of a 1,5-diazabicyclo[6,3,0] dodecane amino acid derivative as a novel dipeptide reverse-turn mimetic , 2006 .

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

[14]  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.

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

[16]  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.

[17]  J. Minna,et al.  Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. , 2007, Cancer cell.

[18]  Ingela Parmryd,et al.  Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. , 2002, Journal of cell science.

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

[20]  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.

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

[22]  R. Korneluk,et al.  XIAP: Apoptotic brake and promising therapeutic target , 2001, Apoptosis.

[23]  J C Reed,et al.  IAP family proteins--suppressors of apoptosis. , 1999, Genes & development.

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

[25]  Xueliang Fang,et al.  Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. , 2004, Analytical biochemistry.