Target Information

Target General Infomation
Target ID
T16739
Former ID
TTDI02104
Target Name
Lysine specific histone demethylase 1
Gene Name
KDM1A
Synonyms
BRAF35HDAC complex protein BHC110; Flavincontaining amine oxidase domaincontaining protein 2; Lysinespecific histone demethylase 1A; KDM1A
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Small-cell lung cancer [ICD9: 162.9; ICD10: C33-C34]
Function
Histone demethylasethat demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoRESTto achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tagfor epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr- 6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E- cadherin/CDH1, CDN7 and KRT8. Required for themaintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7. {ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:17805299, ECO:0000269|PubMed:20228790, ECO:0000269|PubMed:20562920}.
BioChemical Class
Flavin monoamine oxidase
UniProt ID
O60341
EC Number
EC 1.-.-.-
Sequence
MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTP
RKKEPPRASPPGGLAEPPGSAGPQAGPTVVPGSATPMETGIAETPEGRRTSRRKRAKVEY
REMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGVEGAAFQ
SRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEA
PYNSDTVLVHRVHSYLERHGLINFGIYKRIKPLPTKKTGKVIIIGSGVSGLAAARQLQSF
GMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGNPMAVVSKQVNMELAKIKQKC
PLYEANGQAVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQE
KHVKDEQIEHWKKIVKTQEELKELLNKMVNLKEKIKELHQQYKEASEVKPPRDITAEFLV
KSKHRDLTALCKEYDELAETQGKLEEKLQELEANPPSDVYLSSRDRQILDWHFANLEFAN
ATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGC
EVIAVNTRSTSQTFIYKCDAVLCTLPLGVLKQQPPAVQFVPPLPEWKTSAVQRMGFGNLN
KVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWNLYKAPILLALVAGEAAGIMENISD
DVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPI
TPGPSIPGAPQPIPRLFFAGEHTIRNYPATVHGALLSGLREAGRIADQFLGAMYTLPRQA
TPGVPAQQSPSM
Drugs and Mode of Action
Drug(s) GSK2879552 Drug Info Phase 1 Small-cell lung cancer [524597]
Inhibitor GSK-LSD1 Drug Info [543682]
GSK2879552 Drug Info [533290]
Lysine-specific demethylase 1 inhibitors Drug Info [543682]
NCL-1 Drug Info [531332]
OG-L002 Drug Info [532221]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
Pathway Interaction Database Notch signaling pathway
Coregulation of Androgen receptor activity
Notch-mediated HES/HEY network
Reactome HDACs deacetylate histones
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
Factors involved in megakaryocyte development and platelet production
WikiPathways Factors involved in megakaryocyte development and platelet production
Androgen receptor signaling pathway
References
Ref 524597ClinicalTrials.gov (NCT02034123) Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma. U.S. National Institutes of Health.
Ref 531332Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor. Bioorg Med Chem. 2011 Jun 15;19(12):3702-8.
Ref 532221A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. MBio. 2013 Feb 5;4(1):e00558-12.
Ref 533290A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell. 2015 Jul 13;28(1):57-69.
Ref 543682(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2669).

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