Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase.
Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase.
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DOI：
10.1021/jm400351a
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发表时间：
2013-05-09
影响因子：
7.3
通讯作者：
Bachovchin, William W.
中科院分区：
文献类型：
--
作者：
Poplawski, Sarah E.;Lai, Jack H.;Li, Youhua;Jin, Zhiping;Liu, Yuxin;Wu, Wengen;Wu, Yong;Zhou, Yuhong;Sudmeier, James L.;Sanford, David G.;Bachovchin, William W.
成纤维细胞活化蛋白（FAP）是一种丝氨酸蛋白酶，选择性表达于上皮癌的反应性基质成纤维细胞上。它被广泛认为在肿瘤侵袭和转移中起作用，因此代表了一种潜在的癌症新药物靶点。然而，由于目前缺乏选择性抑制剂，对其生物学功能的研究受到阻碍。挑战在于鉴定对FAP具有选择性的抑制剂，所述选择性超过与其共享外肽酶特异性的二肽基肽酶（DPP）和与其共享内肽酶特异性的脯氨酰寡肽酶（PREP）。在这里，我们报道了第一种有效的FAP抑制剂，其选择性超过DPP和PREP，N-（吡啶-4-羰基）-d-Ala-boroPro（ARI-3099，6）。我们还报道了一种类似的有效和选择性PREP抑制剂，N-（吡啶-3-羰基）-Val-boroPro（ARI-3531，22）。两者都是基于硼酸的抑制剂，表明使用这种亲电试剂可以实现高选择性。抑制剂是稳定的，易于合成，并应被证明是有用的，有助于阐明这两个独特的和有趣的酶的生物学功能，以及它们作为药物靶点的潜力。
Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.
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影响因子：
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作者：
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通讯作者：
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