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Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs
Angewandte Chemie International Edition ( IF 16.6 ) Pub Date : 2021-08-20 , DOI: 10.1002/anie.202109237
Robert P Law 1 , Joao Nunes 1 , Chun-Wa Chung 1 , Marcus Bantscheff 2 , Karol Buda 1 , Han Dai 1 , John P Evans 1 , Adam Flinders 1 , Diana Klimaszewska 1 , Antonia J Lewis 1 , Marcel Muelbaier 2 , Paul Scott-Stevens 1 , Peter Stacey 1 , Christopher J Tame 1 , Gillian F Watt 1 , Nico Zinn 2 , Markus A Queisser 1 , John D Harling 1 , Andrew B Benowitz 1
Affiliation  

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.

中文翻译:

高度协作的 FAK 降解 PROTAC 的发现和表征

粘着斑激酶(FAK)是肿瘤进展和转移的关键介质。迄今为止,FAK 抑制剂的临床试验报告的肿瘤适应症疗效令人失望。我们报告了 GSK215 的设计和表征,这是一种基于 VHL E3 连接酶和已知 FAK 抑制剂 VS-4718 的结合剂的强效、选择性、FAK 降解蛋白水解靶向嵌合体 (PROTAC)。X 射线晶体学揭示了高度协作的 FAK-GSK215-VHL 三元复合物的分子基础,与 VS-4718 相比,GSK215 显示出差异化的体外药理学。在小鼠中,单剂量的 GSK215 诱导快速和延长的 FAK 降解,对 FAK 水平产生持久影响(≈96 小时)和显着的 PK/PD 断开。该工具PROTAC分子有望用于体内FAK降解生物学的研究,
更新日期:2021-10-12
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