GSK2801

GSK2801, as an inhibitor of BAZ2A and BAZ2B bromodomains, is potent, selective and cell active acetyl-lysine competitive, with dissociation constants (KD) of 136 and 257 nM for binding to BAZ2B and BAZ2A, respectively [1].

Bromodomains, as protein interaction domains, are acetyl-lysine specific. Bromodomain containing proteins BAZ2A and BAZ2B are closely related. The nucleolar remodeling complex (NoRC) regulates the expression of noncoding RNAs. BAZ2A and BAZ2B constitute the central scaffolding protein of NoRC [1].

In U2OS cells, treatment with the SAHA induced hyperacetylated chromatin. In a GFP-BAZ2A fusion construct, the conserved asparagines that are essential for recognizing the acetylated lysine has been mutated. When a GFP-BAZ2A fusion construct was transfected into SAHA-treated U2OS cells, the mutant construct accelerated FRAP half-recovery time. Treatment with GSK2801 alone in U2OS cells also accelerated FRAP half-recovery time. Both acceleration extents are the same. This meant that GSK2801 can displace BAZ2A from chromatin [1].

Pharmacokinetic parameters of GSK2801 after intraperitoneal and oral dosing to male CD1 mice were measured. Data showed that after oral dosing in vivo, GSK2801 has reasonable exposure, reasonable plasma stability and modest clearance. GSK2801 can be used as an inhibitor of BAZ2A/B bromodomain in vivo [1]. No more in vivo data of the treatment with GSK2801 are found.

Reference:
[1].  Chen P, Chaikuad A, Bamborough P, et al. Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. Journal of medicinal chemistry, 2015.