GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice
Andrew C. Pearce, Mark J. Bamford, Ruth Barber, Angela Bridges, M.A. Convery, Constantinos Demetriou, Siân Evans, Thomas Gobbetti, David J. Hirst, Duncan S. Holmes, Jonathan P. Hutchinson, Sandrine Jayne, Larissa Lezina, Michael T. McCabe, Cassie Messenger, J Morley, Melissa C. Musso, Paul Scott‐Stevens, Ana Sousa Manso, Jennifer Schofield, Tom Slocombe, Don O. Somers, Ann L. Walker, Anastasia Wyce, Xiping Zhang, Simon D. Wagner
Abstract
of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 μg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.