Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain

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• 作者：Apirat Chaikuad ; Steffen Lang ; Paul E. Brennan ; Claudia Temperini ; Oleg Fedorov ; Johan Hollander ; Ruta Nachane ; Chris Abell ; Susanne Müller ; Gregg Siegal ; 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：1648-1653
• 全文大小：468K
• ISSN：1520-4804

文摘

The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.