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

Apirat Chaikuad, Steffen Lang, Paul E Brennan, Claudia Temperini, Oleg Fedorov, Johan Hollander, Ruta Nachane, Chris Abell, Susanne Müller, Gregg Siegal, Stefan Knapp

Journal of medicinal chemistry 2016 Feb 25

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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.

Citation

Apirat Chaikuad, Steffen Lang, Paul E Brennan, Claudia Temperini, Oleg Fedorov, Johan Hollander, Ruta Nachane, Chris Abell, Susanne Müller, Gregg Siegal, Stefan Knapp. Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain. Journal of medicinal chemistry. 2016 Feb 25;59(4):1648-53