Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM9W547)

• DOT Name: Bone morphogenetic protein receptor type-2 (BMPR2)
• Synonyms: BMP type-2 receptor; BMPR-2; EC 2.7.11.30; Bone morphogenetic protein receptor type II; BMP type II receptor; BMPR-II
• Gene Name: BMPR2
• Related Disease:
  Pulmonary arterial hypertension
  Pulmonary hypertension, primary, 1
  Heritable pulmonary arterial hypertension
  Congenital heart disease
• UniProt ID: BMPR2_HUMAN
• PDB ID: 2HLQ; 3G2F; 6UNP; 7PPA; 7PPB; 7PPC; 7U5O
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF00069
• Sequence:
  MTSSLQRPWRVPWLPWTILLVSTAAASQNQERLCAFKDPYQQDLGIGESRISHENGTILC
  SKGSTCYGLWEKSKGDINLVKQGCWSHIGDPQECHYEECVVTTTPPSIQNGTYRFCCCST
  DLCNVNFTENFPPPDTTPLSPPHSFNRDETIIIALASVSVLAVLIVALCFGYRMLTGDRK
  QGLHSMNMMEAAASEPSLDLDNLKLLELIGRGRYGAVYKGSLDERPVAVKVFSFANRQNF
  INEKNIYRVPLMEHDNIARFIVGDERVTADGRMEYLLVMEYYPNGSLCKYLSLHTSDWVS
  SCRLAHSVTRGLAYLHTELPRGDHYKPAISHRDLNSRNVLVKNDGTCVISDFGLSMRLTG
  NRLVRPGEEDNAAISEVGTIRYMAPEVLEGAVNLRDCESALKQVDMYALGLIYWEIFMRC
  TDLFPGESVPEYQMAFQTEVGNHPTFEDMQVLVSREKQRPKFPEAWKENSLAVRSLKETI
  EDCWDQDAEARLTAQCAEERMAELMMIWERNKSVSPTVNPMSTAMQNERNLSHNRRVPKI
  GPYPDYSSSSYIEDSIHHTDSIVKNISSEHSMSSTPLTIGEKNRNSINYERQQAQARIPS
  PETSVTSLSTNTTTTNTTGLTPSTGMTTISEMPYPDETNLHTTNVAQSIGPTPVCLQLTE
  EDLETNKLDPKEVDKNLKESSDENLMEHSLKQFSGPDPLSSTSSSLLYPLIKLAVEATGQ
  QDFTQTANGQACLIPDVLPTQIYPLPKQQNLPKRPTSLPLNTKNSTKEPRLKFGSKHKSN
  LKQVETGVAKMNTINAAEPHVVTVTMNGVAGRNHSVNSHAATTQYANGTVLSGQTTNIVT
  HRAQEMLQNQFIGEDTRLNINSSPDEHEPLLRREQQAGHDEGVLDRLVDRRERPLEGGRT
  NSNNNNSNPCSEQDVLAQGVPSTAADPGPSKPRRAQRPNSLDLSATNVLDGSSIQIGEST
  QDGKSGSGEKIKKRVKTPYSLKRWRPSTWVISTESLDCEVNNNGSNRAVHSKSSTAVYLA
  EGGTATTMVSKDIGMNCL
• Function: On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Can also mediate signaling through the activation of the p38MAPK cascade. Binds to BMP7, BMP2 and, less efficiently, BMP4. Binding is weak but enhanced by the presence of type I receptors for BMPs. Mediates induction of adipogenesis by GDF6.
• Tissue Specificity: Highly expressed in heart and liver.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Axon guidance (hsa04360)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  MicroR.s in cancer (hsa05206)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway: Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[1]
Pulmonary hypertension, primary, 1	DIS6UZY8	Definitive	Autosomal dominant	[2]
Heritable pulmonary arterial hypertension	DISD1Y94	Supportive	Autosomal dominant	[3]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fenfluramine	DM0762O	Phase 3	Bone morphogenetic protein receptor type-2 (BMPR2) increases the response to substance of Fenfluramine.	[21]

17 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 receptor type-2 (BMPR2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[17]
KENPAULLONE	DMAGVXW	Patented	KENPAULLONE increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[18]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[19]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[20]
SU9516	DMQHG0R	Investigative	SU9516 increases the expression of Bone morphogenetic protein receptor type-2 (BMPR2).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin increases the stability of Bone morphogenetic protein receptor type-2 (BMPR2).	[13]

References

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• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
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• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
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• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Altered expression of genes identified in rats with prostatic chronic inflammation in a prostate spheroid model treated by estradiol/testosterone. J Toxicol Sci. 2021;46(11):515-523. doi: 10.2131/jts.46.515.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Simvastatin enhances bone morphogenetic protein receptor type II expression. Biochem Biophys Res Commun. 2006 Jan 6;339(1):59-64. doi: 10.1016/j.bbrc.2005.10.187. Epub 2005 Nov 8.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] 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.
• [19] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [20] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [21] BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002 Sep;20(3):518-23. doi: 10.1183/09031936.02.01762002.