jm6b01566_si_002.csv (0.84 kB)
Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe
dataset
posted on 2016-12-21, 00:00 authored by 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. Prinjhap300/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.