GSK1379725A

GSK1379725A is a selective BPTF ligand with a K_d of 2.8 uM, showing no binding activity for Brd4^[1]. In Vitro: From the NMR titration of GSK1379725A, the bound and unbound resonances are separated by 171 Hz, providing an upper bound for the chemical exchange rate. Assuming an association rate of 1×10⁸ M^-1 s^-1 as a high end for a range of protein-small molecule interactions, (e.g., chymotrypsin: proflavin k₁=1.2×10⁸ M^-1 s^-1), an upper K_d of 8 μM is estimated from this experiment. For a more accurate determination with a non-fluorinated protein, ITC is used as a complementary direct binding assay using unlabeled BPTF. A K_d of 2.8 μM is obtained, consistent with our intermediate exchange resonance broadening by PrOF NMR. Although GSK1379725A has been demonstrated to be selective over Brd4, a full selectivity panel against other bromodomains will be needed. A database search using ChEMBL only showed GSK1379725A to be active in five cellular assays with an EC₅₀ of 500 nM carried out. Additionally, no kinase activity has been reported for GSK1379725A despite the growing screening use of the PKIS library^[1].