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

被引：220

作者：

Cai, Qian ^{[1
,2
,3
,4
]}

Sun, Haiying ^{[1
,2
,3
,4
]}

Peng, Yuefeng ^{[1
,2
,3
,4
]}

Lu, Jianfeng ^{[1
,2
,3
,4
]}

Nikolovska-Coleska, Zaneta ^{[1
,2
,3
,4
]}

McEachern, Donna ^{[1
,2
,3
,4
]}

Liu, Liu ^{[1
,2
,3
,4
]}

Qiu, Su ^{[1
,2
,3
,4
]}

Yang, Chao-Yie ^{[1
,2
,3
,4
]}

Miller, Rebecca ^{[1
,2
,3
,4
]}

Yi, Han ^{[1
,2
,3
,4
]}

Zhang, Tao ^{[5
]}

Sun, Duxin ^{[5
]}

Kang, Sanmao ^{[6
]}

Guo, Ming ^{[6
]}

Leopold, Lance ^{[6
]}

Yang, Dajun ^{[6
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[6] Ascenta Therapeut, Malvern, PA 19355 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 08期

关键词：

MITOCHONDRIA-DERIVED ACTIVATOR; STRUCTURE-BASED DESIGN; X-LINKED INHIBITOR; ALPHA-DEPENDENT APOPTOSIS; CONSTRAINED SMAC MIMETICS; SMALL-MOLECULE MIMETICS; XIAP BIR3 DOMAIN; NF-KAPPA-B; STRUCTURAL BASIS; CASPASE INHIBITION;

D O I：

10.1021/jm101505d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2714 / 2726

页数：13

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