Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases.
A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.
Peng
Yuefeng
Y
Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Sun
Haiying
H
Nikolovska-Coleska
Zaneta
Z
Qiu
Su
S
Yang
Chao-Yie
CY
Lu
Jianfeng
J
Cai
Qian
Q
Yi
Han
H
Kang
Sanmao
S
Yang
Dajun
D
Wang
Shaomeng
S
D000284:Administration, Oral; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases