Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGFN0OD)

• DOT Name: Bone morphogenetic protein receptor type-1B (BMPR1B)
• Synonyms: BMP type-1B receptor; BMPR-1B; EC 2.7.11.30; CD antigen CDw293
• Gene Name: BMPR1B
• Related Disease:
  Brachydactyly type A2
  Isolated Pierre-Robin syndrome
  Syndactyly
  Acromesomelic dysplasia 3
  Adult glioblastoma
  Advanced cancer
  Bone development disease
  Brachydactyly
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Congenital deformities of limbs
  Glioblastoma multiforme
  Immunodeficiency
  Male infertility
  Neoplasm
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Proximal symphalangism 1A
  Pulmonary hypertension
  Schizophrenia
  Brachydactyly type A1D
  Clear cell renal carcinoma
  Coronary heart disease
  Acromesomelic dysplasia 2A
  Acromesomelic dysplasia 2B
  Brachydactyly type A1
  Pulmonary arterial hypertension
  Acromesomelic dysplasia 2C, Hunter-Thompson type
  Asthma
  Brachydactyly type C
  Endometriosis
  Epithelial ovarian cancer
  Female hypogonadism
  Ovarian cancer
  Ovarian neoplasm
  Prostate neoplasm
  Rectal carcinoma
• UniProt ID: BMR1B_HUMAN
• PDB ID: 3MDY
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF07714 ; PF08515
• Sequence:
  MLLRSAGKLNVGTKKEDGESTAPTPRPKVLRCKCHHHCPEDSVNNICSTDGYCFTMIEED
  DSGLPVVTSGCLGLEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVD
  GPIHHRALLISVTVCSLLLVLIILFCYFRYKRQETRPRYSIGLEQDETYIPPGESLRDLI
  EQSQSSGSGSGLPLLVQRTIAKQIQMVKQIGKGRYGEVWMGKWRGEKVAVKVFFTTEEAS
  WFRETEIYQTVLMRHENILGFIAADIKGTGSWTQLYLITDYHENGSLYDYLKSTTLDAKS
  MLKLAYSSVSGLCHLHTEIFSTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVKFISD
  TNEVDIPPNTRVGTKRYMPPEVLDESLNRNHFQSYIMADMYSFGLILWEVARRCVSGGIV
  EEYQLPYHDLVPSDPSYEDMREIVCIKKLRPSFPNRWSSDECLRQMGKLMTECWAHNPAS
  RLTALRVKKTLAKMSESQDIKL
• 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. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction.
• 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)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway: Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brachydactyly type A2	DISUB1OU	Definitive	Autosomal recessive	[1]
Isolated Pierre-Robin syndrome	DISVEHG7	Definitive	Genetic Variation	[2]
Syndactyly	DISZK2BT	Definitive	Genetic Variation	[3]
Acromesomelic dysplasia 3	DIS6IX4H	Strong	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Bone development disease	DISVKAZS	Strong	Biomarker	[6]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[11]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[13]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[5]
Proximal symphalangism 1A	DIS1WSKZ	Strong	Genetic Variation	[14]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[15]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[16]
Brachydactyly type A1D	DISNIL7Q	Moderate	Autosomal dominant	[17]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[18]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[19]
Acromesomelic dysplasia 2A	DISISMZZ	Supportive	Autosomal recessive	[20]
Acromesomelic dysplasia 2B	DISSQNHW	Supportive	Autosomal recessive	[21]
Brachydactyly type A1	DISZUO15	Supportive	Autosomal dominant	[22]
Pulmonary arterial hypertension	DISP8ZX5	Disputed	Unknown	[23]
Acromesomelic dysplasia 2C, Hunter-Thompson type	DISLUZV7	Limited	Genetic Variation	[7]
Asthma	DISW9QNS	Limited	Altered Expression	[24]
Brachydactyly type C	DISZ8FTZ	Limited	Genetic Variation	[14]
Endometriosis	DISX1AG8	Limited	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[12]
Female hypogonadism	DISWASB4	Limited	Biomarker	[25]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[26]
Rectal carcinoma	DIS8FRR7	Limited	Genetic Variation	[27]

4 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 receptor type-1B (BMPR1B).	[28]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Bone morphogenetic protein receptor type-1B (BMPR1B).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Bone morphogenetic protein receptor type-1B (BMPR1B).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bone morphogenetic protein receptor type-1B (BMPR1B).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[33]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[33]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[34]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[35]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[37]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[40]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[41]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[42]
SU9516	DMQHG0R	Investigative	SU9516 increases the expression of Bone morphogenetic protein receptor type-1B (BMPR1B).	[42]

References

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• [2] BMPR1B mutation causes Pierre Robin sequence.Oncotarget. 2017 Apr 18;8(16):25864-25871. doi: 10.18632/oncotarget.16531.
• [3] Novel mutation in the BMPR1B gene (R486L) in a Polish family and further delineation of the phenotypic features of BMPR1B-related brachydactyly.Birth Defects Res A Clin Mol Teratol. 2015 Jun;103(6):567-72. doi: 10.1002/bdra.23354. Epub 2015 Mar 16.
• [4] Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.Cancer Cell. 2008 Jan;13(1):69-80. doi: 10.1016/j.ccr.2007.12.005.
• [5] A miR-125b binding site polymorphism in bone morphogenetic protein membrane receptor type IB gene and prostate cancer risk in China.Mol Biol Rep. 2012 Jan;39(1):369-73. doi: 10.1007/s11033-011-0747-9. Epub 2011 May 10.
• [6] A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies.J Med Genet. 2005 Apr;42(4):314-7. doi: 10.1136/jmg.2004.023564.
• [7] Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility. Eur J Hum Genet. 2018 Jun;26(6):876-885. doi: 10.1038/s41431-018-0121-7. Epub 2018 Mar 26.
• [8] Activation of the pro-migratory bone morphogenetic protein receptor 1B gene in human MDA-MB-468 triple-negative breast cancer cells that over-express CYP2J2.Int J Biochem Cell Biol. 2016 Nov;80:173-178. doi: 10.1016/j.biocel.2016.10.004. Epub 2016 Oct 5.
• [9] MicroRNA-205 Mediates Proteinase-Activated Receptor 2 (PAR(2)) -Promoted Cancer Cell Migration.Cancer Invest. 2017 Oct 21;35(9):601-609. doi: 10.1080/07357907.2017.1378671. Epub 2017 Oct 9.
• [10] Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet. 2009 Apr;84(4):483-92. doi: 10.1016/j.ajhg.2009.03.001. Epub 2009 Mar 26.
• [11] A Selective Cell Population from Dermis Strengthens Bone Regeneration.Stem Cells Transl Med. 2017 Jan;6(1):306-315. doi: 10.5966/sctm.2015-0426. Epub 2016 Aug 8.
• [12] BMPR1B up-regulation via a miRNA binding site variation defines endometriosis susceptibility and CA125 levels.PLoS One. 2013 Dec 5;8(12):e80630. doi: 10.1371/journal.pone.0080630. eCollection 2013.
• [13] Identification of genes for complex diseases using integrated analysis of multiple types of genomic data.PLoS One. 2012;7(9):e42755. doi: 10.1371/journal.pone.0042755. Epub 2012 Sep 5.
• [14] A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2.Eur J Hum Genet. 2006 Dec;14(12):1248-54. doi: 10.1038/sj.ejhg.5201708. Epub 2006 Sep 6.
• [15] Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.Endocrinology. 2004 Sep;145(9):4344-54. doi: 10.1210/en.2004-0234. Epub 2004 Jun 10.
• [16] Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia.Transl Psychiatry. 2018 Nov 23;8(1):252. doi: 10.1038/s41398-018-0304-6.
• [17] 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.
• [18] Downregulation of microRNA-1274a induces cell apoptosis through regulation of BMPR1B in clear cell renal cell carcinoma.Oncol Rep. 2018 Jan;39(1):173-181. doi: 10.3892/or.2017.6098. Epub 2017 Nov 15.
• [19] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [20] Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe. Eur J Hum Genet. 2014 Jun;22(6):726-33. doi: 10.1038/ejhg.2013.222. Epub 2013 Oct 16.
• [21] A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia. Orphanet J Rare Dis. 2015 Jun 24;10:84. doi: 10.1186/s13023-015-0299-5.
• [22] Two novel disease-causing variants in BMPR1B are associated with brachydactyly type A1. Eur J Hum Genet. 2015 Dec;23(12):1640-5. doi: 10.1038/ejhg.2015.38. Epub 2015 Mar 11.
• [23] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [24] Basal expression of bone morphogenetic protein receptor is reduced in mild asthma.Am J Respir Crit Care Med. 2008 May 15;177(10):1074-81. doi: 10.1164/rccm.200709-1376OC. Epub 2008 Feb 21.
• [25] BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency.J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz226. doi: 10.1210/clinem/dgz226.
• [26] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [27] Genetic variation in bone morphogenetic protein and colon and rectal cancer.Int J Cancer. 2012 Feb 1;130(3):653-64. doi: 10.1002/ijc.26047. Epub 2011 Apr 27.
• [28] 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.
• [29] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [32] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [33] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [34] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [35] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [36] Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status. Environ Health Perspect. 2007 Nov;115(11):1646-53. doi: 10.1289/ehp.10283.
• [37] 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.
• [38] 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.
• [39] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [40] 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.
• [41] 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.
• [42] 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.