Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF

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• 作者：James Bennett ; Oleg Fedorov ; Cynthia Tallant ; Octovia Monteiro ; Julia Meier ; Vicky Gamble ; Pavel Savitsky ; Graciela A Nunez-Alonso ; Bernard Haendler ; Catherine Rogers ; Paul E. Brennan ; Susanne Müller ; Stefan Knapp
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1642-1647
• 全文大小：494K
• ISSN：1520-4804

文摘

TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a K_D of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.