7BDE

HUMAN BCL6 BTB-DOMAIN IN COMPLEX WITH GSK137

7BDE の概要

• エントリーDOI: 10.2210/pdb7bde/pdb
• 分子名称: Isoform 2 of B-cell lymphoma 6 protein, 5-[(5S,7R)-3-fluoranyl-7-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl]quinolin-2-amine, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: btb domain, b-cell lymphoma, transcriptional repression transcription, inhibitor, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16101.44

構造登録者

Somers, D.O. (登録日: 2020-12-21, 公開日: 2021-07-28, 最終更新日: 2024-05-01)

主引用文献

Pearce, A.C.,Bamford, M.J.,Barber, R.,Bridges, A.,Convery, M.A.,Demetriou, C.,Evans, S.,Gobbetti, T.,Hirst, D.J.,Holmes, D.S.,Hutchinson, J.P.,Jayne, S.,Lezina, L.,McCabe, M.T.,Messenger, C.,Morley, J.,Musso, M.C.,Scott-Stevens, P.,Manso, A.S.,Schofield, J.,Slocombe, T.,Somers, D.,Walker, A.L.,Wyce, A.,Zhang, X.P.,Wagner, S.D.
GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.
J.Biol.Chem., 297:100928-100928, 2021

PubMed 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 of 8 and a cellular pIC 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.

PubMed: 34274316
DOI: 10.1016/j.jbc.2021.100928

実験手法

X-RAY DIFFRACTION (2.044 Å)