Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe

Philip G. Humphreys, Paul Bamborough, Chun-wa Chung, Peter D. Craggs, Laurie Gordon, Paola Grandi, Thomas G. Hayhow, Jameed Hussain, Katherine L. Jones, Matthew Lindon, Anne-Marie Michon, Jessica F. Renaux, Colin J. Suckling, David F. Tough, Rab K. Prinjha

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.

Original languageEnglish
Pages (from-to)695-709
Number of pages15
JournalJournal of Medicinal Chemistry
Volume60
Issue number2
Early online date9 Jan 2017
DOIs
Publication statusPublished - 26 Jan 2017

Keywords

  • cell membrane permeability
  • histone acetyltransferases
  • membranes

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