Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis,Journal of Medicinal Chemistry

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Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00228
Qi Qi ₁ , Obiamaka Obianyo ₁ , Yuhong Du ₁ , Haian Fu ₁ , Shiyong Li ₁ , Keqiang Ye ₁

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Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure–activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

中文翻译：

天冬酰胺内肽酶的阻滞抑制癌症转移

天冬酰胺内肽酶（AEP），也称为豆蔻素，在各种实体瘤中高度表达，促进癌细胞的侵袭，迁移和转移。已经提出将其作为癌症治疗的预后标志物和治疗靶标。然而，尚未鉴定出针对该蛋白酶的有效的非肽小分子抑制剂。在这里，我们显示黄嘌呤衍生物家族选择性抑制AEP并抑制基质金属蛋白酶（MMP）裂解，从而抑制癌症转移。通过结构-活性关系（SAR）分析，我们获得了抑制乳腺癌侵袭和迁移的优化的铅化合物（38u）。用抑制剂38u对已接种MDA-MB-231细胞的裸鼠进行慢性治疗通过口服给药，剂量依赖性地强烈抑制乳腺癌肺转移，这与AEP阻断MMP-2有关。因此，我们的研究支持38u可能是有效且特异性的AEP抑制剂，可用于治疗癌症。

更新日期：2017-08-18

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