Identification of a selective inhibitor of transforming growth factor β-activated kinase 1 by biosensor-based screening of focused libraries

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• 作者：Takaaki Miura^a ; ^{miuratka@chugai-pharm.co.jp} ; Atsushi Matsuo^b ; Terushige Muraoka^b ; Mitsuaki Ide^b ; Kenji Morikami^b ; Takayuki Kamikawa^a ; Masamichi Nishihara^b ; Hirotaka Kashiwagi^b
• 关键词：TAK1 ; Chemogenomic approach ; Selective Type I inhibitor ; Biophysical screening
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：1031-1036
• 全文大小：1052 K
• 卷排序：27

文摘

Transforming growth factor-β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, plays an essential role in mediating signals from various pro-inflammatory cytokines and therefore may be a good target for developing anti-inflammation agents. Herein, we report our efforts to identify TAK1 inhibitors with a good selectivity profile with which to initiate medicinal chemistry. Instead of resorting to a high-throughput screening campaign, we performed biosensor-based biophysical screening for a limited number of compounds by taking advantage of existing knowledge on kinase inhibitors. Rather than focusing on one specific inhibition mode, we searched for three different types, Type I (ATP-competitive, DFG-in), Type II (DFG-out), and Type III binders (non-ATP competitive) in parallel, and succeeded in identifying candidates in all three categories efficiently and rapidly. Finally, the biosensor-based binding kinetics for the active and inactive forms of TAK1 were measured to prioritize the Type I and Type II inhibitors. The effort resulted in the identification of a new TAK1-selective Type I compound with a thienopyrimidine scaffold that served as a good starting point for medicinal chemistry.