Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYATP2K)

• DOT Name: Bone morphogenetic protein 7 (BMP7)
• Synonyms: BMP-7; Osteogenic protein 1; OP-1; Eptotermin alfa
• Gene Name: BMP7
• Related Disease:
  Multiple congenital anomalies/dysmorphic syndrome
  Hypospadias
• UniProt ID: BMP7_HUMAN
• PDB ID: 1BMP; 1LX5; 1LXI; 1M4U
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MHVRSLRAAAPHSFVALWAPLFLLRSALADFSLDNEVHSSFIHRRLRSQERREMQREILS
  ILGLPHRPRPHLQGKHNSAPMFMLDLYNAMAVEEGGGPGGQGFSYPYKAVFSTQGPPLAS
  LQDSHFLTDADMVMSFVNLVEHDKEFFHPRYHHREFRFDLSKIPEGEAVTAAEFRIYKDY
  IRERFDNETFRISVYQVLQEHLGRESDLFLLDSRTLWASEEGWLVFDITATSNHWVVNPR
  HNLGLQLSVETLDGQSINPKLAGLIGRHGPQNKQPFMVAFFKATEVHFRSIRSTGSKQRS
  QNRSKTPKNQEALRMANVAENSSSDQRQACKKHELYVSFRDLGWQDWIIAPEGYAAYYCE
  GECAFPLNSYMNATNHAIVQTLVHFINPETVPKPCCAPTQLNAISVLYFDDSSNVILKKY
  RNMVVRACGCH
• Function: Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis. Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2A. Once all three components are bound together in a complex at the cell surface, ACVR2A phosphorylates and activates ACVR1. 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 genes. For specific functions such as growth cone collapse in developing spinal neurons and chemotaxis of monocytes, uses also BMPR2 as type II receptor. Can also signal through non-canonical pathways such as P38 MAP kinase signaling cascade that promotes brown adipocyte differentiation through activation of target genes, including members of the SOX family of transcription factors. Promotes the expression of HAMP, this is repressed by its interaction with ERFE.
• Tissue Specificity: Expressed in the kidney and bladder. Lower levels seen in the brain.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Axon guidance (hsa04360)
  Hippo sig.ling pathway (hsa04390)
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Moderate	Autosomal dominant	[1]
Hypospadias	DIS48CCP	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Bone morphogenetic protein 7 (BMP7) affects the response to substance of Cisplatin.	[20]
Paclitaxel	DMLB81S	Approved	Bone morphogenetic protein 7 (BMP7) increases the response to substance of Paclitaxel.	[21]
Mitoxantrone	DMM39BF	Approved	Bone morphogenetic protein 7 (BMP7) affects the response to substance of Mitoxantrone.	[20]

18 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 7 (BMP7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bone morphogenetic protein 7 (BMP7).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Bone morphogenetic protein 7 (BMP7).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bone morphogenetic protein 7 (BMP7).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bone morphogenetic protein 7 (BMP7).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Bone morphogenetic protein 7 (BMP7).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Bone morphogenetic protein 7 (BMP7).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Bone morphogenetic protein 7 (BMP7).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Bone morphogenetic protein 7 (BMP7).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Bone morphogenetic protein 7 (BMP7).	[11]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Bone morphogenetic protein 7 (BMP7).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Bone morphogenetic protein 7 (BMP7).	[13]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Bone morphogenetic protein 7 (BMP7).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Bone morphogenetic protein 7 (BMP7).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bone morphogenetic protein 7 (BMP7).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bone morphogenetic protein 7 (BMP7).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Bone morphogenetic protein 7 (BMP7).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Bone morphogenetic protein 7 (BMP7).	[19]

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 7 (BMP7).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens. J Biochem Mol Toxicol. 2004;18(1):1-11. doi: 10.1002/jbt.20004.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [9] Progesterone decreases bone morphogenetic protein (BMP) 7 expression and BMP7 inhibits decidualization and proliferation in endometrial stromal cells. Hum Reprod. 2010 Mar;25(3):751-6. doi: 10.1093/humrep/dep455. Epub 2010 Jan 18.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [15] 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.
• [16] Repercussions of Bisphenol A on the Physiology of Human Osteoblasts. Int J Mol Sci. 2022 May 11;23(10):5349. doi: 10.3390/ijms23105349.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [21] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.