Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform,Journal of Medicinal Chemistry

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Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01698
Shishir M. Pant ₁ , Amanda Mukonoweshuro ₂ , Bimbisar Desai ₂ , Manoj K. Ramjee ₂ , Christopher N. Selway ₂ , Gary J. Tarver ₂ , Adrian G. Wright ₂ , Kristian Birchall ₃ , Timothy M. Chapman ₃ , Topi A. Tervonen ₁ , Juha Klefström ₁

Affiliation

Hepsin is a membrane-anchored serine protease whose role in hepatocyte growth factor (HGF) signaling and epithelial integrity makes it a target of therapeutic interest in carcinogenesis and metastasis. Using an integrated design, synthesis, and screening platform, we were able to rapidly develop potent and selective inhibitors of hepsin. In progressing from the initial hit 7 to compound 53, the IC₅₀ value against hepsin was improved from ∼1 μM to 22 nM, and the selectivity over urokinase-type plasminogen activator (uPA) was increased from 30-fold to >6000-fold. Subsequent in vitro ADMET profiling and cellular studies confirmed that the leading compounds are useful tools for interrogating the role of hepsin in breast tumorigenesis.

中文翻译：

通过自动闭环优化平台的应用设计，合成和测试有效的选择性肝素抑制剂

肝素是一种膜锚定的丝氨酸蛋白酶，其在肝细胞生长因子（HGF）信号传导和上皮完整性中的作用使其成为癌变和转移的治疗靶标。使用集成的设计，合成和筛选平台，我们能够快速开发出有效的和选择性的肝素抑制剂。从最初的命中7到化合物53的过程中，针对肝素的IC ₅₀值从约1μM提高到22 nM，并且对尿激酶型纤溶酶原激活剂（uPA）的选择性从30倍增加至> 6000倍。随后的体外ADMET分析和细胞研究证实，领先的化合物是用于研究肝素在乳腺肿瘤发生中的作用的有用工具。

更新日期：2018-04-27

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