title: A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment.
abstract: 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.
authors: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Qian
authors: Q
authors: Cai
authors: Haiying
authors: H
authors: Sun
authors: Yuefeng
authors: Y
authors: Peng
authors: Jianfeng
authors: J
authors: Lu
authors: Zaneta
authors: Z
authors: Nikolovska-Coleska
authors: Donna
authors: D
authors: McEachern
authors: Liu
authors: L
authors: Liu
authors: Su
authors: S
authors: Qiu
authors: Chao-Yie
authors: CY
authors: Yang
authors: Rebecca
authors: R
authors: Miller
authors: Han
authors: H
authors: Yi
authors: Tao
authors: T
authors: Zhang
authors: Duxin
authors: D
authors: Sun
authors: Sanmao
authors: S
authors: Kang
authors: Ming
authors: M
authors: Guo
authors: Lance
authors: L
authors: Leopold
authors: Dajun
authors: D
authors: Yang
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001392:Azocines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D001392:Azocines; D001559:Benzhydryl Compounds; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide