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一种在研的用于癌症治疗的多凋亡抑制蛋白（IAP）的有效且口服活性的拮抗剂（SM-406/AT-406）。

A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment.

机构信息

Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.

出版信息

J Med Chem. 2011 Apr 28;54(8):2714-26. doi: 10.1021/jm101505d. Epub 2011 Mar 28.

DOI:10.1021/jm101505d
PMID:21443232
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3520070/
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.

摘要

我们报告了 SM-406（化合物 2）的发现和特性，它是一种有效的、口服生物利用的 Smac 类似物，也是凋亡抑制蛋白（IAPs）的拮抗剂。该化合物与 XIAP、cIAP1 和 cIAP2 蛋白的 K(i)分别为 66.4、1.9 和 5.1 nM。化合物 2 在无细胞功能测定中有效拮抗 XIAP BIR3 蛋白，迅速诱导细胞内 cIAP1 蛋白降解，并抑制多种人癌细胞系中的癌细胞生长。它在小鼠、大鼠、非人灵长类动物和狗中具有良好的口服生物利用度，在异种移植肿瘤中诱导凋亡非常有效，并能够完全抑制肿瘤生长。化合物 2 目前正在进行治疗人类癌症的 I 期临床试验。

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Design of small-molecule Smac mimetics as IAP antagonists.小分子 Smac 模拟物作为 IAP 拮抗剂的设计。
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Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins.非肽类小分子 cIAP-1/2 和 XIAP 蛋白抑制剂。
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IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.IAPs：从细胞胱冬酶抑制剂到 NF-κB、炎症和癌症的调节剂。
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IAP antagonists: promising candidates for cancer therapy.IAP 拮抗剂：癌症治疗的有前途的候选药物。
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Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.三环状、构象受限的半胱天冬酶-2线粒体衍生激活剂小分子模拟物的设计、合成与评估
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