7bde
From Proteopedia
HUMAN BCL6 BTB-DOMAIN IN COMPLEX WITH GSK137
Structural highlights
Disease[BCL6_HUMAN] Note=Chromosomal aberrations involving BCL6 may be a cause of B-cell non-Hodgkin lymphoma. Translocation t(3;14)(q27;q32); translocation t(3;22)(q27;q11) with immunoglobulin gene regions. Note=A chromosomal aberration involving BCL6 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with POU2AF1/OBF1. Note=A chromosomal aberration involving BCL6 may be a cause of lymphoma. Translocation t(3;4)(q27;p11) with ARHH/TTF. Function[BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.[1] [2] Publication Abstract from PubMedBCL6 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 mug/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. GSK137, a potent small molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.,Pearce AC, Bamford MJ, Barber R, Bridges A, Convery MA, Demetriou C, Evans S, Gobbetti T, Hirst DJ, Holmes DS, Hutchinson JP, Jayne S, Lezina L, McCabe MT, Messenger C, Morley J, Musso MC, Scott-Stevens P, Manso AS, Schofield J, Slocombe T, Somers D, Walker AL, Wyce A, Zhang XP, Wagner SD J Biol Chem. 2021 Jul 15:100928. doi: 10.1016/j.jbc.2021.100928. PMID:34274316[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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