Details of Drug Off-Target (DOT)

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

• DOT Name: Noggin (NOG)
• Gene Name: NOG
• Related Disease:
  Melanoma
  Multiple synostoses syndrome 1
  NOG-related symphalangism spectrum disorder
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Alzheimer disease
  Ankylosing spondylitis
  Brachydactyly
  Breast cancer
  Breast carcinoma
  Glioma
  Graft-versus-host disease
  High blood pressure
  Holoprosencephaly
  Immunodeficiency
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Neural tube defect
  Non-insulin dependent diabetes
  Obesity
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Stroke
  Syndactyly
  Synostosis
  Craniosynostosis
  Female hypogonadism
  Glioblastoma multiforme
  Myelofibrosis
  Osteoarthritis
  Primary myelofibrosis
  Brachydactyly type B2
  Multiple synostoses syndrome
  Proximal symphalangism
  Stapes ankylosis with broad thumbs and toes
  Tarsal-carpal coalition syndrome
  Plasma cell myeloma
  Type-1/2 diabetes
  Fibrodysplasia ossificans progressiva
  Proximal symphalangism 1A
• UniProt ID: NOGG_HUMAN
• PDB ID: 1M4U; 7AG0
• Pfam ID: PF05806
• Sequence:
  MERCPSLGVTLYALVVVLGLRATPAGGQHYLHIRPAPSDNLPLVDLIEHPDPIFDPKEKD
  LNETLLRSLLGGHYDPGFMATSPPEDRPGGGGGAAGGAEDLAELDQLLRQRPSGAMPSEI
  KGLEFSEGLAQGKKQRLSKKLRRKLQMWLWSQTFCPVLYAWNDLGSRFWPRYVKVGSCFS
  KRSCSVPEGMVCKPSKSVHLTVLRWRCQRRGGQRCGWIPIQYPIISECKCSC
• Function: Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. Essential for cartilage morphogenesis and joint formation. Inhibits chondrocyte differentiation through its interaction with GDF5 and, probably, GDF6.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  Formation of paraxial mesoderm (R-HSA-9793380)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Multiple synostoses syndrome 1	DISD179V	Definitive	Autosomal dominant	[2]
NOG-related symphalangism spectrum disorder	DISEOUIO	Definitive	Autosomal dominant	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Ankylosing spondylitis	DISRC6IR	Strong	Biomarker	[7]
Brachydactyly	DIS2533F	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[11]
High blood pressure	DISY2OHH	Strong	Biomarker	[12]
Holoprosencephaly	DISR35EC	Strong	Genetic Variation	[13]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
leukaemia	DISS7D1V	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[16]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[17]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[22]
Stroke	DISX6UHX	Strong	Biomarker	[23]
Syndactyly	DISZK2BT	Strong	Genetic Variation	[24]
Synostosis	DISXGMZW	Strong	Biomarker	[25]
Craniosynostosis	DIS6J405	moderate	Biomarker	[26]
Female hypogonadism	DISWASB4	moderate	Altered Expression	[27]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[28]
Myelofibrosis	DISIMP21	moderate	Biomarker	[29]
Osteoarthritis	DIS05URM	moderate	Biomarker	[30]
Primary myelofibrosis	DIS6L0CN	moderate	Biomarker	[29]
Brachydactyly type B2	DIS6CYYN	Supportive	Autosomal dominant	[31]
Multiple synostoses syndrome	DISGA3UA	Supportive	Autosomal dominant	[32]
Proximal symphalangism	DISK9LH5	Supportive	Autosomal dominant	[2]
Stapes ankylosis with broad thumbs and toes	DISGVQR4	Supportive	Autosomal dominant	[33]
Tarsal-carpal coalition syndrome	DISY90L2	Supportive	Autosomal dominant	[34]
Plasma cell myeloma	DIS0DFZ0	Disputed	Biomarker	[35]
Type-1/2 diabetes	DISIUHAP	Disputed	Altered Expression	[18]
Fibrodysplasia ossificans progressiva	DISAT6WU	Limited	Genetic Variation	[8]
Proximal symphalangism 1A	DIS1WSKZ	Limited	Genetic Variation	[36]

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 Noggin (NOG).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Noggin (NOG).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Noggin (NOG).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Noggin (NOG).	[39]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Noggin (NOG).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Noggin (NOG).	[41]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Noggin (NOG).	[42]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Noggin (NOG).	[41]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Noggin (NOG).	[41]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Noggin (NOG).	[41]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Noggin (NOG).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Noggin (NOG).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Noggin (NOG).	[46]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Noggin (NOG).	[47]

References

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• [2] Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet. 2001 Dec;60(6):447-51. doi: 10.1034/j.1399-0004.2001.600607.x.
• [3] 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.
• [4] Crucial role of carbonic anhydrase IX in tumorigenicity of xenotransplanted adult T-cell leukemia-derived cells.Cancer Sci. 2017 Mar;108(3):435-443. doi: 10.1111/cas.13163.
• [5] Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression.Cancer Sci. 2012 Jun;103(6):1145-54. doi: 10.1111/j.1349-7006.2012.02252.x. Epub 2012 Apr 3.
• [6] The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer's disease.Ageing Res Rev. 2013 Jan;12(1):157-64. doi: 10.1016/j.arr.2012.05.002. Epub 2012 Jun 12.
• [7] Enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis: a study based on a three-dimensional biomimetic environment.Cell Death Dis. 2019 Apr 25;10(5):350. doi: 10.1038/s41419-019-1586-1.
• [8] Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance.PLoS One. 2012;7(4):e35062. doi: 10.1371/journal.pone.0035062. Epub 2012 Apr 18.
• [9] Human Immune System Increases Breast Cancer-Induced Osteoblastic Bone Growth in a Humanized Mouse Model without Affecting Normal Bone.J Immunol Res. 2019 May 9;2019:4260987. doi: 10.1155/2019/4260987. eCollection 2019.
• [10] Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence.Brain Pathol. 2016 Jan;26(1):43-61. doi: 10.1111/bpa.12263. Epub 2015 May 19.
• [11] Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses.Cell Mol Immunol. 2018 Nov;15(11):953-962. doi: 10.1038/cmi.2017.106. Epub 2017 Nov 20.
• [12] Negative autoregulation of BMP dependent transcription by SIN3B splicing reveals a role for RBM39.Sci Rep. 2016 Jun 21;6:28210. doi: 10.1038/srep28210.
• [13] Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients.Mol Genet Metab. 2012 Jun;106(2):241-3. doi: 10.1016/j.ymgme.2012.03.008. Epub 2012 Mar 21.
• [14] Establishment of a myeloid leukemia cell line, TRL-01, with MLL-ENL fusion gene.Cancer Genet Cytogenet. 2006 Aug;169(1):1-11. doi: 10.1016/j.cancergencyto.2005.09.008.
• [15] Lung tumor-associated osteoblast-derived bone morphogenetic protein-2 increased epithelial-to-mesenchymal transition of cancer by Runx2/Snail signaling pathway.J Biol Chem. 2011 Oct 28;286(43):37335-46. doi: 10.1074/jbc.M111.256156. Epub 2011 Sep 1.
• [16] Myelination in Multiple Sclerosis Lesions Is Associated with Regulation of Bone Morphogenetic Protein 4 and Its Antagonist Noggin.Int J Mol Sci. 2019 Jan 3;20(1):154. doi: 10.3390/ijms20010154.
• [17] A novel mutation in the gene encoding noggin is not causative in human neural tube defects.J Neurogenet. 2002 Jan-Mar;16(1):65-71.
• [18] The low levels of bone morphogenic protein-4 and its antagonist noggin in type 2 diabetes.Hormones (Athens). 2018 Jun;17(2):247-253. doi: 10.1007/s42000-018-0041-5. Epub 2018 Jun 26.
• [19] Noggin depletion in adipocytes promotes obesity in mice.Mol Metab. 2019 Jul;25:50-63. doi: 10.1016/j.molmet.2019.04.004. Epub 2019 Apr 10.
• [20] Denosumab effects on serum levels of the bone morphogenetic proteins antagonist noggin in patients with transfusion-dependent thalassemia and osteoporosis.Hematology. 2019 Dec;24(1):318-324. doi: 10.1080/16078454.2019.1570617.
• [21] The BMP antagonist Noggin is produced by osteoblasts in response to the presence of prostate cancer cells.Biotechnol Appl Biochem. 2018 May;65(3):407-418. doi: 10.1002/bab.1619. Epub 2017 Nov 2.
• [22] The prognostic significance of BMP-6 signaling in prostate cancer.Mod Pathol. 2008 Dec;21(12):1436-43. doi: 10.1038/modpathol.2008.94. Epub 2008 Oct 17.
• [23] Bioinformatic gene analysis for potential biomarkers and therapeutic targets of atrial fibrillation-related stroke.J Transl Med. 2019 Feb 13;17(1):45. doi: 10.1186/s12967-019-1790-x.
• [24] Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment.Int J Pediatr Otorhinolaryngol. 2018 May;108:208-212. doi: 10.1016/j.ijporl.2018.03.008. Epub 2018 Mar 14.
• [25] P35S mutation in the NOG gene associated with Teunissen-Cremers syndrome and features of multiple NOG joint-fusion syndromes.Eur J Med Genet. 2008 Jul-Aug;51(4):351-7. doi: 10.1016/j.ejmg.2008.02.008. Epub 2008 Mar 20.
• [26] Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model.Orthod Craniofac Res. 2009 Aug;12(3):254-62. doi: 10.1111/j.1601-6343.2009.01460.x.
• [27] Premature ovarian failure in a female with proximal symphalangism and Noggin mutation.Fertil Steril. 2004 Apr;81(4):1137-9. doi: 10.1016/j.fertnstert.2003.08.054.
• [28] Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction.PLoS One. 2016 Jul 8;11(7):e0158639. doi: 10.1371/journal.pone.0158639. eCollection 2016.
• [29] Increased SLAMF7(high) monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab.Blood. 2019 Sep 5;134(10):814-825. doi: 10.1182/blood.2019000051. Epub 2019 Jul 3.
• [30] Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues.J Orthop Res. 2017 Aug;35(8):1671-1682. doi: 10.1002/jor.23463. Epub 2016 Nov 8.
• [31] A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet. 2007 Aug;81(2):388-96. doi: 10.1086/519697. Epub 2007 Jun 8.
• [32] Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am J Med Genet A. 2010 Jun;152A(6):1540-4. doi: 10.1002/ajmg.a.33387.
• [33] Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet. 2002 Sep;71(3):618-24. doi: 10.1086/342067. Epub 2002 Jun 27.
• [34] Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med. 2001 Sep-Oct;3(5):349-53. doi: 10.1097/00125817-200109000-00004.
• [35] Multimodal Bioluminescent and Positronic-emission Tomography/Computational Tomography Imaging of Multiple Myeloma Bone Marrow Xenografts in NOG Mice.J Vis Exp. 2019 Jan 7;(143):10.3791/58056. doi: 10.3791/58056.
• [36] Identification of a Novel NOG Missense Mutation in a Chinese Family With Symphalangism and Tarsal Coalitions.Front Genet. 2019 Apr 18;10:353. doi: 10.3389/fgene.2019.00353. eCollection 2019.
• [37] 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.
• [38] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [39] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [40] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [41] 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.
• [42] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [43] 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.
• [44] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [45] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [46] 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.
• [47] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.