成纤维细胞活化蛋白
化学
二肽
酶抑制剂
IC50型
酶
药理学
生物化学
体外
组合化学
氨基酸
癌症
内科学
医学
作者
Tsung Ying Tsai,Teng‐Kuang Yeh,Xin Chen,Tsu Hsu,Yu‐Chen Jao,Chih‐Hsiang Huang,Jen‐Shin Song,Yu‐Chen Huang,Chia‐Hui Chien,Jing-Huai Chiu,Shih-Chieh Yen,Hung‐Kuan Tang,Yu‐Sheng Chao,Weir‐Torn Jiaang
摘要
Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC50 of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC50 > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.
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