Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9WN536)

• DOT Name: Bone morphogenetic protein 6 (BMP6)
• Synonyms: BMP-6; VG-1-related protein; VG-1-R; VGR-1
• Gene Name: BMP6
• Related Disease: Hemochromatosis type 5
• UniProt ID: BMP6_HUMAN
• PDB ID: 2QCW; 2R52; 2R53; 6OMO
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MPGLGRRAQWLCWWWGLLCSCCGPPPLRPPLPAAAAAAAGGQLLGDGGSPGRTEQPPPSP
  QSSSGFLYRRLKTQEKREMQKEILSVLGLPHRPRPLHGLQQPQPPALRQQEEQQQQQQLP
  RGEPPPGRLKSAPLFMLDLYNALSADNDEDGASEGERQQSWPHEAASSSQRRQPPPGAAH
  PLNRKSLLAPGSGSGGASPLTSAQDSAFLNDADMVMSFVNLVEYDKEFSPRQRHHKEFKF
  NLSQIPEGEVVTAAEFRIYKDCVMGSFKNQTFLISIYQVLQEHQHRDSDLFLLDTRVVWA
  SEEGWLEFDITATSNLWVVTPQHNMGLQLSVVTRDGVHVHPRAAGLVGRDGPYDKQPFMV
  AFFKVSEVHVRTTRSASSRRRQQSRNRSTQSQDVARVSSASDYNSSELKTACRKHELYVS
  FQDLGWQDWIIAPKGYAANYCDGECSFPLNAHMNATNHAIVQTLVHLMNPEYVPKPCCAP
  TKLNAISVLYFDDNSNVILKKYRNMVVRACGCH
• Function: Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation. Also plays an important role in the regulation of HAMP/hepcidin expression and iron metabolism by acting as a ligand for hemojuvelin/HJV. Also acts to promote expression of HAMP, potentially via the interaction with its receptor BMPR1A/ALK3. Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2B. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target. Can also signal through non-canonical pathway such as TAZ-Hippo signaling cascade to modulate VEGF signaling by regulating VEGFR2 expression.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
  Ovarian steroidogenesis (hsa04913)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemochromatosis type 5	DISAUGYR	Supportive	Autosomal dominant	[1]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Bone morphogenetic protein 6 (BMP6).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bone morphogenetic protein 6 (BMP6).	[17]

48 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bone morphogenetic protein 6 (BMP6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bone morphogenetic protein 6 (BMP6).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bone morphogenetic protein 6 (BMP6).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bone morphogenetic protein 6 (BMP6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bone morphogenetic protein 6 (BMP6).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Bone morphogenetic protein 6 (BMP6).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bone morphogenetic protein 6 (BMP6).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Bone morphogenetic protein 6 (BMP6).	[11]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Bone morphogenetic protein 6 (BMP6).	[12]
Mebendazole	DMO14SG	Approved	Mebendazole increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Flutamide	DMK0O7U	Approved	Flutamide increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Amodiaquine	DME4RA8	Approved	Amodiaquine increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Etodolac	DM6WJO9	Approved	Etodolac increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Zafirlukast	DMHNQOG	Approved	Zafirlukast increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Trazodone	DMK1GBJ	Approved	Trazodone increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Bromfenac	DMKB79O	Approved	Bromfenac increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Ethambutol	DMR87LC	Approved	Ethambutol decreases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Fludrocortisone	DMUDIR8	Approved	Fludrocortisone decreases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Lumiracoxib	DM1S4AG	Approved	Lumiracoxib increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Trihexyphenidyl	DMB19L8	Approved	Trihexyphenidyl increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Procyclidine	DMHFJDT	Approved	Procyclidine increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Penbutolol	DM4ES8F	Approved	Penbutolol increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Levofloxacin	DMS60RB	Approved	Levofloxacin decreases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Biperiden	DME78OA	Approved	Biperiden increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Diphenhydramine	DMKQTBA	Approved	Diphenhydramine decreases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Alpidem	DMN7Y9K	Approved	Alpidem increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Aminosalicylic acid	DMENSL5	Approved	Aminosalicylic acid increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Pirprofen	DMMOFHT	Approved	Pirprofen increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Protriptyline	DMNHTZI	Approved	Protriptyline increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Bone morphogenetic protein 6 (BMP6).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Bone morphogenetic protein 6 (BMP6).	[14]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Bone morphogenetic protein 6 (BMP6).	[15]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Bone morphogenetic protein 6 (BMP6).	[16]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Bone morphogenetic protein 6 (BMP6).	[16]
Ticrynafen	DMLFSTR	Withdrawn from market	Ticrynafen increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Nimesulide	DMR1NMD	Terminated	Nimesulide increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bone morphogenetic protein 6 (BMP6).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Bone morphogenetic protein 6 (BMP6).	[19]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Bone morphogenetic protein 6 (BMP6).	[20]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Bone morphogenetic protein 6 (BMP6).	[14]
IPRONIAZIDE	DM42ENF	Investigative	IPRONIAZIDE increases the expression of Bone morphogenetic protein 6 (BMP6).	[10]

References

• [1] Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans. Gastroenterology. 2016 Mar;150(3):672-683.e4. doi: 10.1053/j.gastro.2015.10.049. Epub 2015 Nov 12.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [4] Human oligodendrocytes derived from embryonic stem cells: Effect of noggin on phenotypic differentiation in vitro and on myelination in vivo. Mol Cell Neurosci. 2007 Mar;34(3):310-23. doi: 10.1016/j.mcn.2006.11.008. Epub 2006 Dec 28.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [11] 2,3,7,8-tetrachlorodibenzo-p-dioxin augments the modulation of gene expression mediated by the thyroid hormone receptor. Toxicol Appl Pharmacol. 2004 Feb 1;194(3):201-10. doi: 10.1016/j.taap.2003.09.010.
• [12] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [15] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [16] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.