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

Andrew C Pearce,Cassie Messenger,Constantinos Demetriou,Larissa Lezina,Anastasia Wyce,Jonathan P Hutchinson,Duncan S Holmes,Melissa C Musso,Ann L Walker,Sandrine Jayne,Ana Sousa Manso,Thomas Gobbetti,Michael T Mccabe,Mark J Bamford,Ruth Barber,Tom Slocombe,Angela Bridges,Simon D Wagner,J A Schofield ,David Hirst ,J Morley ,Paul Scott‐Stevens ,Don O Somers ,M.a Convery ,Siân Evans ,Xiping Zhang

doi:10.1016/j.jbc.2021.100928

Abstract

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB–POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. 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 corepressor 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 of 8 and a cellular pIC50 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.

Highlights

(BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain and, in turn, recruit histone deacetylases
To identify chemical starting points for inhibiting B-cell lymphoma 6 (BCL6) consideration was given to the fact that the desired mechanism of action was to antagonise the binding of BCL6 to its BTB-POZ domain binding co-repressors, preserving function of other parts of the protein
The ability of GSK137 to inhibit binding of intracellular full-length human BCL6 to BCL6-binding domain of SMRT in live cells was measured by NanoBret assay, and pIC50 was determined to be 7.3 (Table 1)

Summary

Introduction

(BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain and, in turn, recruit histone deacetylases. We carried out a pharmacokinetic analysis of GSK137 and an in vivo study 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.

Results

Conclusion