Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC0Y6E0)

• DOT Name: Bone morphogenetic protein 5 (BMP5)
• Synonyms: BMP-5
• Gene Name: BMP5
• Related Disease:
  Adrenal cortex neoplasm
  Adrenocortical carcinoma
  Autoimmune disease
  Benign prostatic hyperplasia
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Fibrodysplasia ossificans progressiva
  Major depressive disorder
  Osteoarthritis
  Precancerous condition
  Relapsing-remitting multiple sclerosis
  Schwannoma
  Squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Hirschsprung disease
  Neoplasm
  Creutzfeldt Jacob disease
  Multiple sclerosis
  Rheumatoid arthritis
• UniProt ID: BMP5_HUMAN
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MHLTVFLLKGIVGFLWSCWVLVGYAKGGLGDNHVHSSFIYRRLRNHERREIQREILSILG
  LPHRPRPFSPGKQASSAPLFMLDLYNAMTNEENPEESEYSVRASLAEETRGARKGYPASP
  NGYPRRIQLSRTTPLTTQSPPLASLHDTNFLNDADMVMSFVNLVERDKDFSHQRRHYKEF
  RFDLTQIPHGEAVTAAEFRIYKDRSNNRFENETIKISIYQIIKEYTNRDADLFLLDTRKA
  QALDVGWLVFDITVTSNHWVINPQNNLGLQLCAETGDGRSINVKSAGLVGRQGPQSKQPF
  MVAFFKASEVLLRSVRAANKRKNQNRNKSSSHQDSSRMSSVGDYNTSEQKQACKKHELYV
  SFRDLGWQDWIIAPEGYAAFYCDGECSFPLNAHMNATNHAIVQTLVHLMFPDHVPKPCCA
  PTKLNAISVLYFDDSSNVILKKYRNMVVRSCGCH
• Function: Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cartilage and bone formation or neurogenesis. Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2. 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. Can also signal through non-canonical pathway such as MAPK p38 signaling cascade to promote chondrogenic differentiation. Promotes the expression of HAMP, this is repressed by its interaction with ERFE.
• Tissue Specificity: Expressed in the lung and liver.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenal cortex neoplasm	DISO17X1	Strong	Altered Expression	[1]
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Genetic Variation	[4]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[4]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[4]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Fibrodysplasia ossificans progressiva	DISAT6WU	Strong	Altered Expression	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[7]
Precancerous condition	DISV06FL	Strong	Biomarker	[8]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Altered Expression	[9]
Schwannoma	DISTTVLA	Strong	Altered Expression	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	moderate	Biomarker	[11]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[11]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[11]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	Disputed	Biomarker	[13]
Creutzfeldt Jacob disease	DISCB6RX	Limited	Altered Expression	[14]
Multiple sclerosis	DISB2WZI	Limited	Altered Expression	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[15]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Bone morphogenetic protein 5 (BMP5) affects the response to substance of Temozolomide.	[27]
DTI-015	DMXZRW0	Approved	Bone morphogenetic protein 5 (BMP5) affects the response to substance of DTI-015.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Bone morphogenetic protein 5 (BMP5).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bone morphogenetic protein 5 (BMP5).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Bone morphogenetic protein 5 (BMP5).	[17]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Bone morphogenetic protein 5 (BMP5).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bone morphogenetic protein 5 (BMP5).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Bone morphogenetic protein 5 (BMP5).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Bone morphogenetic protein 5 (BMP5).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Bone morphogenetic protein 5 (BMP5).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Bone morphogenetic protein 5 (BMP5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Bone morphogenetic protein 5 (BMP5).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bone morphogenetic protein 5 (BMP5).	[23]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Bone morphogenetic protein 5 (BMP5).	[24]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Bone morphogenetic protein 5 (BMP5).	[25]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of Bone morphogenetic protein 5 (BMP5).	[26]

References

• [1] Bone morphogenetic proteins 2 and 5 are down-regulated in adrenocortical carcinoma and modulate adrenal cell proliferation and steroidogenesis.Cancer Res. 2009 Jul 15;69(14):5784-92. doi: 10.1158/0008-5472.CAN-08-4428. Epub 2009 Jul 7.
• [2] Genome-wide study reveals an important role of spontaneous autoimmunity, cardiomyocyte differentiation defect and anti-angiogenic activities in gender-specific gene expression in Keshan disease.Chin Med J (Engl). 2014;127(1):72-8.
• [3] Genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis.JCI Insight. 2019 May 16;5(12):e129749. doi: 10.1172/jci.insight.129749.
• [4] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [5] Over-expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification: a new syndrome.Am J Med Genet A. 2007 Apr 1;143A(7):699-706. doi: 10.1002/ajmg.a.31649.
• [6] Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression.J Psychopharmacol. 2013 Oct;27(10):915-20. doi: 10.1177/0269881113499829. Epub 2013 Aug 7.
• [7] Evaluation of the association between a single-nucleotide polymorphism of bone morphogenetic proteins 5 gene and risk of knee osteoarthritis.J Postgrad Med. 2017 Jul-Sep;63(3):151-156. doi: 10.4103/jpgm.JPGM_450_16.
• [8] Overexpression of BMP-2/4, -5 and BMPR-IA associated with malignancy of oral epithelium.Oral Oncol. 2001 Apr;37(3):225-33. doi: 10.1016/s1368-8375(00)00087-7.
• [9] High serum levels of BMP-2 correlate with BMP-4 and BMP-5 levels and induce reduced neuronal phenotype in patients with relapsing-remitting multiple sclerosis.J Neuroimmunol. 2017 Sep 15;310:120-128. doi: 10.1016/j.jneuroim.2017.07.008. Epub 2017 Jul 15.
• [10] Transcriptional mRNA of BMP-2, 3, 4 and 5 in trigeminal nerve, benign and malignant peripheral nerve sheath tumors.Histol Histopathol. 2001 Oct;16(4):1013-9. doi: 10.14670/HH-16.1013.
• [11] Epithelial-to-mesenchymal transition induced by TGF-1 is mediated by Blimp-1-dependent repression of BMP-5.Cancer Res. 2012 Dec 1;72(23):6268-78. doi: 10.1158/0008-5472.CAN-12-2270. Epub 2012 Oct 10.
• [12] Expression analysis of BMP2, BMP5, BMP10 in human colon tissues from Hirschsprung disease patients.Int J Clin Exp Pathol. 2014 Jan 15;7(2):529-36. eCollection 2014.
• [13] MiR-32 promotes tumorigenesis of colorectal cancer by targeting BMP5.Biomed Pharmacother. 2018 Oct;106:1046-1051. doi: 10.1016/j.biopha.2018.07.050. Epub 2018 Jul 17.
• [14] Detection of two transforming growth factor-beta-related morphogens, bone morphogenetic proteins-4 and -5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions.Acta Neuropathol. 1995;90(1):76-9. doi: 10.1007/BF00294462.
• [15] Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.Arthritis Res Ther. 2006;8(3):R58. doi: 10.1186/ar1923. Epub 2006 Mar 15.
• [16] 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.
• [17] 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.
• [18] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [25] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [26] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.
• [27] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.