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.