Details of Drug Off-Target (DOT)

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

• DOT Name: Bone morphogenetic protein 4 (BMP4)
• Synonyms: BMP-4; Bone morphogenetic protein 2B; BMP-2B
• Gene Name: BMP4
• Related Disease:
  Microphthalmia with brain and digit anomalies
  Stickler syndrome
  Renal agenesis, unilateral
  Orofacial cleft 11
• UniProt ID: BMP4_HUMAN
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MIPGNRMLMVVLLCQVLLGGASHASLIPETGKKKVAEIQGHAGGRRSGQSHELLRDFEAT
  LLQMFGLRRRPQPSKSAVIPDYMRDLYRLQSGEEEEEQIHSTGLEYPERPASRANTVRSF
  HHEEHLENIPGTSENSAFRFLFNLSSIPENEVISSAELRLFREQVDQGPDWERGFHRINI
  YEVMKPPAEVVPGHLITRLLDTRLVHHNVTRWETFDVSPAVLRWTREKQPNYGLAIEVTH
  LHQTRTHQGQHVRISRSLPQGSGNWAQLRPLLVTFGHDGRGHALTRRRRAKRSPKHHSQR
  ARKKNKNCRRHSLYVDFSDVGWNDWIVAPPGYQAFYCHGDCPFPLADHLNSTNHAIVQTL
  VNSVNSSIPKACCVPTELSAISMLYLDEYDKVVLKNYQEMVVEGCGCR
• Function: Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis. Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction. Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2. Once all three components are bound together in a complex at the cell surface, BMPR2 phosphorylates and activates BMPR1A. In turn, BMPR1A propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target genes. Positively regulates the expression of odontogenic development regulator MSX1 via inducing the IPO7-mediated import of SMAD1 to the nucleus. Required for MSX1-mediated mesenchymal molar tooth bud development beyond the bud stage, via promoting Wnt signaling. Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, expression is repressed during the bell stage by MSX1-mediated inhibition of CTNNB1 signaling. Able to induce its own expression in dental mesenchymal cells and also in the neighboring dental epithelial cells via an MSX1-mediated pathway. Can also signal through non-canonical BMP pathways such as ERK/MAP kinase, PI3K/Akt, or SRC cascades. For example, induces SRC phosphorylation which, in turn, activates VEGFR2, leading to an angiogenic response.
• Tissue Specificity: Expressed in the lung and lower levels seen in the kidney. Present also in normal and neoplastic prostate tissues, and prostate cancer cell lines.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Thyroid hormone sig.ling pathway (hsa04919)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Germ layer formation at gastrulation (R-HSA-9754189)
  Formation of lateral plate mesoderm (R-HSA-9758920)
  Formation of intermediate mesoderm (R-HSA-9761174)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Specification of primordial germ cells (R-HSA-9827857)
  Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microphthalmia with brain and digit anomalies	DISYZ63U	Definitive	Autosomal dominant	[1]
Stickler syndrome	DISQWFHN	Moderate	Autosomal recessive	[2]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[3]
Orofacial cleft 11	DISKFZG7	Limited	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Bone morphogenetic protein 4 (BMP4) decreases the response to substance of Methotrexate.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Bone morphogenetic protein 4 (BMP4).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bone morphogenetic protein 4 (BMP4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bone morphogenetic protein 4 (BMP4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bone morphogenetic protein 4 (BMP4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bone morphogenetic protein 4 (BMP4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bone morphogenetic protein 4 (BMP4).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Bone morphogenetic protein 4 (BMP4).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Bone morphogenetic protein 4 (BMP4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Bone morphogenetic protein 4 (BMP4).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bone morphogenetic protein 4 (BMP4).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bone morphogenetic protein 4 (BMP4).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Bone morphogenetic protein 4 (BMP4).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Bone morphogenetic protein 4 (BMP4).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Bone morphogenetic protein 4 (BMP4).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Bone morphogenetic protein 4 (BMP4).	[18]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Bone morphogenetic protein 4 (BMP4).	[19]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Bone morphogenetic protein 4 (BMP4).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Bone morphogenetic protein 4 (BMP4).	[15]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Bone morphogenetic protein 4 (BMP4).	[20]
Adenosine	DMM2NSK	Approved	Adenosine increases the expression of Bone morphogenetic protein 4 (BMP4).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bone morphogenetic protein 4 (BMP4).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Bone morphogenetic protein 4 (BMP4).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Bone morphogenetic protein 4 (BMP4).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bone morphogenetic protein 4 (BMP4).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bone morphogenetic protein 4 (BMP4).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Bone morphogenetic protein 4 (BMP4).	[28]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Bone morphogenetic protein 4 (BMP4).	[29]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Bone morphogenetic protein 4 (BMP4).	[30]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the expression of Bone morphogenetic protein 4 (BMP4).	[21]
Naringin	DM4DG1Y	Investigative	Naringin increases the expression of Bone morphogenetic protein 4 (BMP4).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bone morphogenetic protein 4 (BMP4).	[25]

References

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• [19] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
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• [21] Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
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• [28] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
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• [30] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
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• [32] Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factor-superfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness. J Rheumatol. 2010 Feb;37(2):246-56. doi: 10.3899/jrheum.090167. Epub 2009 Dec 15.