Humphreys, Philip G. Bamborough, Paul Chung, Chun-wa D. Craggs, Peter Gordon, Laurie Grandi, Paola Hayhow, Thomas G. Hussain, Jameed Jones, Katherine L. Lindon, Matthew Michon, Anne-Marie Renaux, Jessica F. Suckling, Colin J. F. Tough, David Prinjha, Rab K. Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe 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. 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
    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
10.1021/acs.jmedchem.6b01566.s001