Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

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• 作者：Haiying Sun ; Zaneta Nikolovska-Coleska ; Jianfeng Lu ; Jennifer L. Meagher ; Chao-Yie Yang ; Su Qiu ; York Tomita ; Yumi Ueda ; Sheng Jiang ; Krzysztof Krajewski ; Peter P. Roller ; Jeanne A. Stuckey ; Shaomeng W
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：December 12, 2007
• 年：2007
• 卷：129
• 期：49
• 页码：15279 - 15294
• 全文大小：775K
• 年卷期：v.129,no.49(December 12, 2007)
• ISSN：1520-5126

文摘

XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectorscaspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein inits dimeric form effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains.We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds toXIAP containing both BIR domains with an IC₅₀ value of 1.39 nM, being 300 and 7000 times more potentthan its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrentlyinteracts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis atconcentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding,functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smacmimetics.