GSK2801 is a potent, selective, orally active and cell active acetyl-lysine competitive BAZ2A and BAZ2B bromodomains inhibitor with K_d values of 136 nM and 257 nM, respectively. GSK2801 shows >50-fold selectivity for BAZ2A/B over BRD4^[1]. IC50 & Target: Kd: 136 nM (BAZ2A) and 257 nM (BAZ2B)^[1] In Vitro: GSK2801 binds TAF1L(2) with an affinity K_B of 0.31μM (K_D: 3.2 μM) and a binding enthalpy change ΔH of −8.6 kcal/mol. ITC experiments using the bromodomain of BRD9 results in the determination of an affinity K_B of 0.826 μM (K_D: 1.1 μM) and ΔH of −9.8 kcal/mol^[1].
GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. In 2D cultures, enhances displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induces cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC^[2]. In Vivo: In order to determine the suitability of GSK2801 for in vivo experiments, pharmacokinetic parameters after intraperitoneal and oral dosing to male CD1 mice is measured. GSK2801 has reasonable in vivo exposure after oral dosing, modest clearance, and reasonable plasma stability^[1].