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

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 pIC 50 of 8 and a cellular pIC 50 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.

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays

“…In addition, 17, 2, 11, 14 and 15 all mimic interactions with main chain atoms from both corepressors by forming H-bond networks (direct or water-mediated) with one or more of the following BCL6 residues: Asn21, Arg24 or Arg28. Several of the BCL6-ligand interactions observed for our HTS hits, such as the intercalation between Tyr58 and Asn21, the key H-bond to Met51, the H-bond to Glu115, and the interactions with Arg24 and Arg28, are also present in reported BCL6 inhibitors with different chemical scaffolds binding in the same hotspot 17,18,[20][21][22][23][24]32,33 , which is not surprising as they all mimic the interactions observed with the SMRT and BCOR corepressors.…”

“…Disruption of the SMRT or BCOR corepressor interaction with the BCL6 BTB domain is sufficient to inhibit DLBCL cell growth 9,13 . Consequently, we and others have sought to discover small molecule inhibitors that disrupt these interactions, aiming at identifying new treatments for BCL6-driven lymphomas, and multiple small molecule inhibitors have now been reported for BCL6 [14][15][16][17][18][19][20][21][22][23][24] .…”

Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment

“…B-cell lymphoma 6 (BCL6), a transcriptional repressor protein, is a potential drug target for non-Hodgkin's lymphoma 47 , 48 . Several small molecule inhibitors and peptides of BCL6 with in vivo efficacy can only work at high concentrations, limiting their clinical application 49 , 50 , 51 .…”

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

“…In pursuit of the development of potent and selective BCL6 inhibitors, 1.7 million structurally diverse GSK compounds were screened by using TR-FRET, and 17 (GSK137) was reported as an inhibitor that bound competitively to the BCL6 BTB-POZ domain (Scheme 4B). 112 The TR-FRET assay showed that 17 suppressed the binding of BCL6 with SMRT, nuclear receptor corepressor 1, and BCL6 corepressor with pIC 50 values of 8.0, 7.6, and 7.6 in vitro, respectively. The X-ray crystal structure of the complex showed that 17 can directly bind to the BTB domain of BCL6, the two nitrogen atoms on aminoquinoline formed hydrogen bonds with Glu115, and the nitrogen atom of the amino group on tetrahydropyrazolo[1,5a]pyrimidine formed hydrogen bonds with Met51.…”

“…In pursuit of the development of potent and selective BCL6 inhibitors, 1.7 million structurally diverse GSK compounds were screened by using TR-FRET, and 17 ( GSK137 ) was reported as an inhibitor that bound competitively to the BCL6 BTB-POZ domain (Scheme B) . The TR-FRET assay showed that 17 suppressed the binding of BCL6 with SMRT, nuclear receptor corepressor 1, and BCL6 corepressor with pIC 50 values of 8.0, 7.6, and 7.6 in vitro , respectively.…”