title: Structure-based design of potent, conformationally constrained Smac mimetics.
abstract: A successful structure-based design and synthesis of a class of highly potent conformationally constrained Smac mimetics is described. The most potent compound has a Ki value of 25 nM binding to the XIAP BIR3 protein and is 23 times more potent than natural Smac peptides. These potent Smac mimetics can serve as powerful chemical and pharmacological tools to further elucidate the role of Smac and its cellular binding partners in apoptosis regulation and may be developed as a new class of anti-cancer drugs.
authors.affiliation: Departments of Internal Medicine and Medicinal Chemistry and Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
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; D001667:Binding, Competitive; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; 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; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D005047:Etoposide