title: Structure-based design, synthesis and biochemical testing of novel and potent Smac peptido-mimetics.
abstract: Structure-based design, chemical synthesis and biochemical testing of a series of novel Smac peptido-mimetics as inhibitors of XIAP protein are described. The most potent compound, 6j, has a binding affinity (K(i) value) of 24 nM to XIAP BIR3 protein and is 24 times more potent than the native Smac AVPI peptide. Further optimization of these potent Smac mimetics may ultimately lead to the development of a novel class of anticancer drugs for the treatment of human cancer by overcoming apoptosis-resistance of cancer cells through targeting the inhibitor of apoptosis proteins.
authors.affiliation: University of Michigan Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Hongguang
authors.initials: H
authors.lastname: Pan
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human