Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase,ACS Chemical Biology

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Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-06-13 00:00:00 , DOI: 10.1021/acschembio.8b00250
Expédite Yen-Pon ₁ , Bo Li ₁ , Marta Acebrón-Garcia-de-Eulate ₂ , Céline Tomkiewicz-Raulet ₃ , John Dawson ₄ , Daniel Lietha ₂ , Margaret C Frame ₄ , Xavier Coumoul ₃ , Christiane Garbay ₁ , Mélanie Etheve-Quelquejeu ₁ , Huixiong Chen ₁

Affiliation

Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor.

中文翻译：

首个不可逆的粘着斑激酶抑制剂的基于结构的设计、合成和表征

粘着斑激酶信号通路及其功能参与了肿瘤恶性肿瘤的发展和侵袭性，是一个有前景的癌症治疗靶点。已经开发了几种可逆的 FAK 抑制剂并正在进行临床试验。另一方面，不可逆共价抑制剂将带来许多理想的药理学特征，包括高效力和延长作用持续时间。在此，我们报告了第一个高效且不可逆的 FAK 激酶抑制剂的结构引导开发。该抑制剂在鳞状细胞癌中显示出非常有效的 FAK 自身磷酸化降低。

更新日期：2018-06-13

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