Development of Peptidomimetics Targeting IAPs

Sharma, Sushil; Straub, Christopher; Zawel, Leigh

doi:10.1007/s10989-005-9003-2

Cited by 54 publications

(67 citation statements)

References 43 publications

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“…Our results show that LBW242 induces activation of caspase-9, casapse-8, and caspase-3 ( Figure 5B-D). LBW242 eliminates the inhibitory effect of XIAP on caspase-9, thereby resulting in activation of caspase-9-mediated apoptotic cascade; 7,33 in concert with these findings, our data show that LBW242 induces caspase-9 activation in MM cells. Interestingly, LBW242 also triggers caspase-8 activation, which is consistent with a previous report.…”

Section: Mechanisms Mediating Anti-mm Activity Of Smac Mimeticsupporting

confidence: 76%

“…33 The functional specificity of LBW242 was determined using a FRET-based competition assay. In this assay, the ability of LBW242 to compete with biotinylated Smac for occupancy of the XIAP BIR3 binding pocket is assessed ("Materials and methods").…”

Section: Chemical Structure and Xiap (Bir3) Binding Activity Of Smac mentioning

confidence: 99%

“…[32][33][34][35][36] Our prior studies have shown that various anti-MM agents down-regulate IAPs; 37 however, whether or not direct inhibition of XIAP by a Smac mimetic could trigger apoptosis in these cells is undefined.…”

Section: Introductionmentioning

confidence: 99%

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Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)

Chauhan

Neri

Velankar

et al. 2006

Blood

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136

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IntroductionTumor cell responses to chemotherapy include growth arrest and apoptosis. 1 Stress-induced apoptosis 2-4 is associated with alterations in mitochondrial membrane permeabilization and release of several apoptogenic factors, such as cytochrome c (cyto c), 5,6 Smac/DIABLO, 7,8 AIF, 9 EndoG, 10 and HtrA2/Omi. 11 Once released into the cytosol, these mitochondrial proteins trigger both caspase-dependent (by cyto c or second mitochondria-derived activator of caspases [Smac]) and caspase-independent (by AIF or Endo-G) apoptosis. Conversely, inhibitors of apoptosis proteins (IAPs) block the enzymatic activity of caspases that mediate cell death, 12,13 and overexpression of IAPs confers chemoresistance in various tumor types. [14][15][16] Recent studies have shown that the mitochondrial apoptotic protein Smac can abrogate the protective function of IAPs, such as X-linked inhibitor of apoptosis (XIAP). 7,8 XIAP is the most potent caspase inhibitor among IAPs and binds with initiator caspase-9 and executioner caspases 3 and 7 through its BIR3 and BIR2 domains, respectively. 17,18 Stress stimuli trigger the release of Smac from mitochondria into the cytosol, where it binds to and eliminates its inhibitory effect on caspase-9, thereby resulting in activation of caspase-9-mediated apoptotic signaling cascade. 7,[19][20][21] These findings suggest the potential clinical utility of Smac mimetics to trigger apoptosis and overcome drug resistance conferred by IAPs.There are several additional rationales for using Smac mimetic as a potential therapy. First, the cell-permeable Smac peptides, when combined with chemotherapy, inhibited tumor growth in vivo with little toxicity in mice. [22][23][24][25] Second, our prior studies have established that Smac release is critical during most anti-multiple myeloma (MM) agent-induced apoptosis, and that dysfunctional Smac release may, in part, contribute to the development of drug resistance. 26 Third, defects in the mitochondrial apoptotic machinery includes up-regulated antiapoptotic protein Bcl-2, which inhibits Smac activity. 26 Smac mimetics have the ability to circumvent the requirement for mitochondrial processing and release of Smac, thereby potentially triggering apoptosis even in Bcl-2-overexpressing MM cells. Fourth, MM cells have constitutively activated NF-B growth/survival signaling, 27-31 and a Smac mimetic was shown to potentiate apoptosis in TNF-␣-treated cells despite NF-B activation. 32 Thus, Smac agonists are promising candidates as novel cytotoxic therapies in MM.Several groups have succeeded in developing potent, smallmolecular-weight Smac mimetic compounds with high affinity for the BIR3 domain of IAPs at pharmacologically achievable concentrations. [32][33][34][35][36] Our prior studies have shown that various anti-MM agents down-regulate IAPs; 37 however, whether or not direct inhibition of XIAP by a Smac mimetic could trigger apoptosis in these cells is undefined. For personal use only. on May 9, 2018. by guest www.bloodjournal.org FromIn the present st...

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Section: Mechanisms Mediating Anti-mm Activity Of Smac Mimeticsupporting

confidence: 76%

Section: Chemical Structure and Xiap (Bir3) Binding Activity Of Smac mentioning

confidence: 99%

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Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)

Chauhan

Neri

Velankar

et al. 2006

Blood

Self Cite

136

View full text Add to dashboard Cite

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“…1). We and others have generated small-molecule Smac mimetics anticipating efficacy in cancer based on reinstitution of apoptotic signaling (2)(3)(4). The available data suggest that there is significant similarity in the structural and biochemical activities of the current generation of Smac mimetic small molecules (2,3,5).…”

Section: Introductionmentioning

confidence: 99%

A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

et al. 2007

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Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor A (TNFA) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFA signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFA induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFA-mediated apoptosis.

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“…These antagonists possess proapoptotic activity both in vitro and in vivo. [24][25][26][27][28] Smacmimetics induce the degradation of cIAP1 and/or cIAP2 in complex I, resulting in the formation of the prodeath complex II, which promotes cancer cell death. Moreover and key to the current study, this process has an absolute requirement for TNF-a.…”

mentioning

confidence: 99%

Smac-Mimetic–Induced Epithelial Cell Death Reduces the Growth of Renal Cysts

Fan

Zhou

Sweeney

et al. 2013

Journal of the American Society of Nephrology

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Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-a and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-a accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac-mimetic selectively induces TNF-a-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-a augmented the formation and activation of the RIPK1-dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-a in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD.

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Development of Peptidomimetics Targeting IAPs

Cited by 54 publications

References 43 publications

Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)

Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)

A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling

Smac-Mimetic–Induced Epithelial Cell Death Reduces the Growth of Renal Cysts

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