GSK4027

GSK4027 is a potent inhibitor of the bromodomain of PCAF and GCN5 with good selectivity over other BRD-containing proteins. GSK4027 has good aqueous solubility, cell permeability, and it shows cellular target engagement of PCAF as measured in a NanoBRET assay (IC50=60 nM). GSK4027 is non-cytotoxic up to 200 uM. GSK4027 (R,R-enantiomer) is partnered with the enantiomeric negative control GSK4028 (S,S-enantiomer). L-Moses represents an orthogonal chemical probe.

GSK4027 represents an orthogonal method to inhibit binding of the bromodomains present in PCAF and GCN5 to their targets compared with L-Moses. This compound shows similar in vitro and cellular potency to L-Moses (~50 nM) but was developed on an entirely different structural scaffold. The compound shows good target engagement in a nanoBRET assay against full-length PCAF and excellent selectivity versus other bromodomains, including BRD4 (>10,000-fold) and BRPF2, BRPF3, and BPTF (>70-fold). Compared with L-Moses, this compound showed a stronger response in the cellular target-engagement assays, and its use should take priority over L-Moses. GSK4028 serves as a reliable negative control. As with L-Moses, the one caveat to GSK4027 is that it is difficult to distinguish between effects on PCAF and GCN5 with this inhibitor.