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- W2245158538 abstract "PR-2 XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac/DIABLO (second mitochondria-derived activator of caspase or direct IAP binding protein with low pI), a protein released from mitochondria in response to apoptotic stimuli, in its dimeric form effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. We designed, synthesized and evaluated a series of non-peptide, cell-permeable, bivalent small-molecules which mimics Smac protein for targeting XIAP. SM-164 is one of the most potent Smac mimetics we have designed. Our binding and gel filtration studies shows SM-164 concurrently targets both the BIR2 and BIR3 domains in XIAP and binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000-times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. In our cell-free caspases functional assays, SM-164 completely restores the activity of caspase-9 and caspases-3 and -7 inhibited by XIAP at the same molar concentraction as XIAP. In cell-based assays, SM-164 effectively induces apoptosis at concentrations as low as 1 nM in several cancer cell lines and has a minimal toxicity to normal cells at 10,000 nM. The potency of SM-164 in binding, functional and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics." @default.
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- W2245158538 date "2007-11-01" @default.
- W2245158538 modified "2023-09-22" @default.
- W2245158538 title "Design, synthesis, and evaluation of bivalent conformationally constrained Smac mimetics that concurrently targeting both BIR2 and BIR3 domain of XIAP" @default.
- W2245158538 hasPublicationYear "2007" @default.
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