2. Academic Validation
  3. GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice

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

  • J Biol Chem. 2021 Aug;297(2):100928. doi: 10.1016/j.jbc.2021.100928.
Andrew C Pearce 1,  Mark J Bamford 1,  Ruth Barber 2,  Angela Bridges 1,  Maire A Convery 1,  Constantinos Demetriou 3,  Sian Evans 2,  Thomas Gobbetti 1,  David J Hirst 1,  Duncan S Holmes 1,  Jonathan P Hutchinson 1,  Sandrine Jayne 3,  Larissa Lezina 4,  Michael T McCabe 5,  Cassie Messenger 1,  Joanne Morley 1,  Melissa C Musso 5,  Paul Scott-Stevens 1,  Ana Sousa Manso 4,  Jennifer Schofield 2,  Tom Slocombe 1,  Don Somers 1,  Ann L Walker 1,  Anastasia Wyce 5,  Xi-Ping Zhang 5,  Simon D Wagner 6
Affiliations

Affiliations

  • 1 GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • 2 Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK.
  • 3 Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK.
  • 4 Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK; Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK.
  • 5 GlaxoSmithKline, Collegeville, Pennsylvania, USA.
  • 6 Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK. Electronic address: [email protected].
PMID: 34274316 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.

Keywords

BCL6; BCL6 inhibitor; antibody response; autoimmunity; drug discovery; immunology; lymphocyte; lymphoma.

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