A Potent and Orally Active Antagonist (SM-406/AT-406) of Multiple Inhibitor of Apoptosis Proteins (IAPs) in Clinical Development for Cancer Treatment

• Published in: Journal of medicinal chemistry Vol. 54; no. 8; pp. 2714 - 2726
• Main Authors: Cai, Qian, Sun, Haiying, Peng, Yuefeng, Lu, Jianfeng, Nikolovska-Coleska, Zaneta, McEachern, Donna, Liu, Liu, Qiu, Su, Yang, Chao-Yie, Miller, Rebecca, Yi, Han, Zhang, Tao, Sun, Duxin, Kang, Sanmao, Guo, Ming, Leopold, Lance, Yang, Dajun, Wang, Shaomeng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.04.2011; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Area Under Curve; Azocines - pharmacokinetics; Azocines - pharmacology; Azocines - therapeutic use; Benzhydryl Compounds - pharmacokinetics; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Biological Availability; Cell Line, Tumor; Chemistry, Medicinal; Humans; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Life Sciences & Biomedicine; Models, Molecular; Neoplasms - drug therapy; Pharmacology & Pharmacy; Science & Technology; SMALL-MOLECULE MIMETICS; X-LINKED INHIBITOR; MITOCHONDRIA-DERIVED ACTIVATOR; XIAP BIR3 DOMAIN; STRUCTURAL BASIS; ALPHA-DEPENDENT APOPTOSIS; CASPASE INHIBITION; CONSTRAINED SMAC MIMETICS; NF-KAPPA-B; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101505d

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K i of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.