- Debio-1143: Inhibitor of apoptosis protein (IAP) antagonist Cancer therapy
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Inhibitors of apoptosis proteins (IAPs) block caspases, modulate nuclear factor NF-êB signaling pathways and are involved in resistance to cancer therapies. Debio-1143, a mimetic of an endogenous IAP inhibitor (second mitochondriaderived activator of caspases [SMAC]), may help to overcome treatment resistance and has demonstrated antitumor activity in various cancer cell lines and xenograft models, alone or in combination with chemotherapy, radiotherapy or immunotherapies. So far, about 150 cancer patients have been enrolled in 5 registered early-phase clinical trials testing Debio-1143. Tolerability was acceptable even when the drug was used in combination therapies. In monotherapy, pharmacokinetics was linear, but varied considerably among patients in combination settings. High tumor penetration and on-target activity were consistently shown in patient surrogate tissues and tumor biopsies. Tumor responses to second-(or higher) line monotherapy in patients with various advanced cancers were rather weak, but currently followed approaches as an adjunct to existing cancer therapies look encouraging. Still, to identify ideal target populations and concomitant regimens remains challenging.
- Ray-Coquard,Bourhis,Delord,Vuagniaux,Zanna,Lu,Wang
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p. 745 - 755
(2018/03/21)
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- BIVALENT DIAZO BICYCLIC SMAC MIMETICS AND THE USES THEREOF
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The invention relates to diazo bicyclic Smac mimetics that are tethered through a covalent linker to give a bivalent species. Bivalent diazo bicyclic Smac mimetics function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs). The invention also relate
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Page/Page column 64
(2011/05/06)
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- DIAZO BICYCLIC SMAC MIMETICS AND THE USES THEREOF
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The invention relates to diazo bicyclic mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.
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Page/Page column 35
(2010/12/26)
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- HETEROARYL-SUBSTITUTED BICYCLIC SMAC MIMETICS AND THE USES THEREOF
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The invention relates to heteroaryl-substituted bicyclic mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.
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- BIVALENT SMAC MIMETICS AND THE USES THEREOF
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The invention relates to bivalent mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosi
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Page/Page column 92-93
(2008/06/13)
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