GSK137 is a potent, small-molecule BCL6 inhibitor binding to BCL6 BTB-POZ domain, displaces peptides derived from the human SMRT co-repressor from the BCL6 BTB-POZ domain in a TR-FRET assay with a pIC50 of 8.0.
GSK137 also displaced peptides from human nuclear receptor co-repressor 1 and BCL6 co-repressor corepressors, which bind in the same position as SMRT, both with a pIC50 of 7.6.
GSK137 showed potency against mouse and rat BCL6 and SMRTwith pIC50 to be 7.8 and 7.6, respectively, inhibited binding of intracellular full-length human BCL6 to BCL6-binding domain of SMRT (residues 1292–1500) in live cells with pIC50 of 7.3.
GSK137 antagonizes the binding of corepressors to BCL6 in cell-free and whole cell assays without causing loss of BCL6 protein.
GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines.
GSK137 demonstrated reduction in specific antibody titers in response to immunization with T-dependent antigens at drug levels consistent with robust engagement with the BCL6 BTB-POZ domain target in vivo.