Design, synthesis, and evaluation of potent, nonpeptidic mimetics of second mitochondria-derived activator of caspases.
A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K(i) of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC(50) of 8.9 nM.
Sun
Wei
W
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China.
Nikolovska-Coleska
Zaneta
Z
Qin
Dongguang
D
Sun
Haiying
H
Yang
Chao-Yie
CY
Bai
Longchuang
L
Qiu
Su
S
Wang
You
Y
Ma
Dawei
D
Wang
Shaomeng
S
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins / Q000138:chemical synthesis*; D024101:Mitochondrial Proteins / Q000138:chemical synthesis*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C412403:DIABLO protein, human; C538797:DM-28 compound; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D000409:Alanine