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GSK137, a potent small molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice

Authors: Pearce, Andrew C.; Bamford, Mark J.; Barber, Ruth; Bridges, Angela; Convery, Maire A.; Demetriou, Constantinos; Evans, Sian; Gobbetti, Thomas; Hirst, David J.; Holmes, Duncan S.; Hutchinson, Jonathan P.; Jayne, Sandrine; Lezina, Larissa; McCabe, Michael T.; Messenger, Cassie; Morley, Joanne; Musso, Melissa C.; Scott-Stevens, Paul; Manso, Ana Sousa; Schofield, Jennifer; Slocombe, Tom; Somers, Don; Walker, Ann L.; Wyce, Anastasia; Zhang, Xi-Ping; Wagner, Simon D.

Online: https://www.sciencedirect.com/science/article/pii/S0021925821007286

Issue: J Biol Chem. 2021 Aug;297(2):100928.


BCL6 is a zinc finger transcriptional repressor possessing a BTB-POZ domain, which is required for homodimerization and association with co-repressors. BCL6 has multiple roles in normal immunity, autoimmunity and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high affinity antibody responses to T-dependent antigens. The co-repressor binding groove in the BTB-POZ domain is a potential target for small compound mediated therapy. Several inhibitors targeting this binding groove have been described but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 = 8 and a cellular pIC50 = 7.3 for blocking binding of a peptide derived from the co-repressor silencing mediator for retinoid or thyroid-hormone receptors (SMRT) 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 IgG responses and reduced numbers of germinal centers and germinal center B-cells following immunisation of mice with the hapten trinitro-phenol (TNP). Overall, we report a novel small molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.