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*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1648-1653
Number of pages6
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
DOIs
Publication statusPublished - 25 Feb 2016
Externally publishedYes

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