title: Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP.
abstract: 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 protein in its 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 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. SM-164 concurrently interacts 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 at concentrations 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 Smac mimetics.
authors.affiliation: Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Meagher
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Su
authors.initials: S
authors.lastname: Qiu
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ueda
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001667:Binding, Competitive; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases