Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases

• Published in: Journal of medicinal chemistry Vol. 51; no. 24; pp. 8158 - 8162
• Main Authors: Peng, Yuefeng, Sun, Haiying, Nikolovska-Coleska, Zaneta, Qiu, Su, Yang, Chao-Yie, Lu, Jianfeng, Cai, Qian, Yi, Han, Kang, Sanmao, Yang, Dajun, Wang, Shaomeng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.12.2008; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Baculoviral IAP Repeat-Containing 3 Protein; Biological and medical sciences; Caspase Inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Chemistry, Pharmaceutical - methods; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General aspects; Humans; Inhibitor of Apoptosis Proteins - chemistry; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Mitochondria - enzymology; Mitochondria - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein - chemistry; CANCER-CELLS; TARGET; SMAC/DIABLO; XIAP BIR3 DOMAIN; STRUCTURAL BASIS; ALPHA-DEPENDENT APOPTOSIS; ANTAGONISTS; BINDING; IAP PROTEINS; STRUCTURE-BASED DESIGN; Human; Rat; Mimetic; Rodentia; Lactam; Oral administration; Bioavailability; In vitro; Second mitochondria derived activator of caspase protein; Biological activity; Vertebrata; Mammalia; Cell line; Apoptosis inhibitory protein; Animal; Mammary gland; Small molecule; Pharmacokinetics; Chemical synthesis; Tumor cell; Apoptosis
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm801254r

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 IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.