Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site.
A successful structure-based design of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a Ki of 350 nM for binding to the XIAP BIR3 domain protein. 12d is found to be effective in enhancing apoptosis induced by cisplatin in PC-3 human prostate cancer cells.
Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.
Haiying
H
Sun
Zaneta
Z
Nikolovska-Coleska
Chao-Yie
CY
Yang
Liang
L
Xu
York
Y
Tomita
Krzysztof
K
Krajewski
Peter P
PP
Roller
Shaomeng
S
Wang
D020816:Amino Acid Motifs; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000737:chemistry*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003500:Cyclization; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; D006574:Heterocyclic Compounds, 2-Ring; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases