10.1021/acs.jmedchem.6b01566.s001 Philip G. Humphreys Philip G. Humphreys Paul Bamborough Paul Bamborough Chun-wa Chung Chun-wa Chung Peter D. Craggs Peter D. Craggs Laurie Gordon Laurie Gordon Paola Grandi Paola Grandi Thomas G. Hayhow Thomas G. Hayhow Jameed Hussain Jameed Hussain Katherine L. Jones Katherine L. Jones Matthew Lindon Matthew Lindon Anne-Marie Michon Anne-Marie Michon Jessica F. Renaux Jessica F. Renaux Colin J. Suckling Colin J. Suckling David F. Tough David F. Tough Rab K. Prinjha Rab K. Prinjha Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe American Chemical Society 2016 PCAF inflammation pathways GSK 4028 report GSK 4027 selectivity multidomain proteins control nonderepressible 5 chemical probe bromodomain families nonselective pyridazinone GCN BET family C-terminal bromodomain Cell Penetrant target engagement cancer development 2016-12-21 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_Potent_Cell_Penetrant_and_Selective_p300_CBP-Associated_Factor_PCAF_General_Control_Nonderepressible_5_GCN5_Bromodomain_Chemical_Probe/4531073 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.