TY - JOUR
T1 - Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe
AU - Humphreys, Philip G.
AU - Bamborough, Paul
AU - Chung, Chun-wa
AU - Craggs, Peter D.
AU - Gordon, Laurie
AU - Grandi, Paola
AU - Hayhow, Thomas G.
AU - Hussain, Jameed
AU - Jones, Katherine L.
AU - Lindon, Matthew
AU - Michon, Anne-Marie
AU - Renaux, Jessica F.
AU - Suckling, Colin J.
AU - Tough, David F.
AU - Prinjha, Rab K.
PY - 2017/1/26
Y1 - 2017/1/26
N2 - 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.
AB - 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.
KW - cell membrane permeability
KW - histone acetyltransferases
KW - membranes
UR - http://www.scopus.com/inward/record.url?scp=85010715473&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b01566
DO - 10.1021/acs.jmedchem.6b01566
M3 - Article
C2 - 28002667
AN - SCOPUS:85010715473
SN - 0022-2623
VL - 60
SP - 695
EP - 709
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -