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lysine demethylase 6B

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2685

Nomenclature: lysine demethylase 6B

Family: 1.14.11.- Histone demethylases

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1643 17p13.1 KDM6B lysine demethylase 6B
Mouse - 1641 11 B3 Kdm6b KDM1 lysine (K)-specific demethylase 6B
Rat - 1361 10q24 Kdm6b lysine demethylase 6B
Previous and Unofficial Names Click here for help
JMJD3 | KDM1 lysine (K)-specific demethylase 6B | lysine (K)-specific demethylase 6B
Database Links Click here for help
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GSK-J1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 – 7.6 pIC50 6-7
pIC50 7.2 – 7.6 (IC50 6x10-8 – 2.8x10-8 M) [6-7]
compound 3 [PMID: 29633584] Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 5.8 pIC50 5
pIC50 5.8 (IC50 1.52x10-6 M) [5]
IOX1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.8 pIC50 9
pIC50 5.8 (IC50 1.6x10-6 M) [9]
GSK-J4 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.1 pIC50 6
pIC50 5.1 (IC50 8.6x10-6 M) [6]
Immunopharmacology Comments
In relation to the immune system, overexpression of KDM6B (JMJD3) is associated with inflammation [3-4] and with immune cell cancers such as T‐cell acute lymphoblastic leukemia and Hodgkin's lymphoma [1,8]. Selective KDM6B inhibitors which restore H3K27 tri-methylation marks on KDM6B transcriptional target genes are being developed e.g. Compound 3 [PMID: 29633584], with clinical efficacy applicable to the treatment of cancer, inflammation and neurological disorders being the ultimate goal.

KDM6A and KDM6B have been reported as key regulators of metabolic switches that are involved in metabolic reprogramming of human T helper cell subsets [2]. In vitro, inhibition by GSK-J4 (the ester prodrug of GSK-J1, a KDM6A/B inhibitor) increases repressive H3K27me3 histone marks which causes down-regulation of the key transcription factor RORγt during Th17 differentiation, and in mature Th17 cells leads to metabolic reprogramming, suppression of IL-17 cytokine levels and reduced proliferation. This work suggests that inhibiting KDM6 demethylases may be an effective intervention in autoimmune inflammation.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002437 inflammatory response to antigenic stimulus IEA
GO:0006954 inflammatory response IEA

References

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1. Anderton JA, Bose S, Vockerodt M, Vrzalikova K, Wei W, Kuo M, Helin K, Christensen J, Rowe M, Murray PG et al.. (2011) The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma. Oncogene, 30 (17): 2037-43. [PMID:21242977]

2. Cribbs AP, Terlecki-Zaniewicz S, Philpott M, Baardman J, Ahern D, Lindow M, Obad S, Oerum H, Sampey B, Mander PK et al.. (2020) Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism. Proc. Natl. Acad. Sci. U.S.A., 117 (11): 6056-6066. [PMID:32123118]

3. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S et al.. (2009) Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J., 28 (21): 3341-52. [PMID:19779457]

4. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell, 130 (6): 1083-94. [PMID:17825402]

5. Giordano A, Del Gaudio F, Johansson C, Riccio R, Oppermann U, Di Micco S. (2018) Virtual Fragment Screening Identification of a Quinoline-5,8-dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor. ChemMedChem, 13 (12): 1160-1164. [PMID:29633584]

6. Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV, Boesen T, Labelle M, Gerlach LO, Birk P, Helin K. (2014) Inhibition of demethylases by GSK-J1/J4. Nature, 514 (7520): E1-2. [PMID:25279926]

7. Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H et al.. (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature, 488 (7411): 404-8. [PMID:22842901]

8. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, Loizou E, Holmfeldt L, Strikoudis A, King B et al.. (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature, 514 (7523): 513-7. [PMID:25132549]

9. Schiller R, Scozzafava G, Tumber A, Wickens JR, Bush JT, Rai G, Lejeune C, Choi H, Yeh TL, Chan MC et al.. (2014) A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1. ChemMedChem, 9 (3): 566-71. [PMID:24504543]

How to cite this page

1.14.11.- Histone demethylases: lysine demethylase 6B. Last modified on 04/03/2020. Accessed on 25/02/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2685.