Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB7KQKV)

• DOT Name: Transmembrane glycoprotein NMB (GPNMB)
• Synonyms: Hematopoietic growth factor inducible neurokinin-1 type
• Gene Name: GPNMB
• Related Disease: Amyloidosis, primary localized cutaneous, 3
• UniProt ID: GPNMB_HUMAN
• Pfam ID: PF20433 ; PF18911
• Sequence:
  MECLYYFLGFLLLAARLPLDAAKRFHDVLGNERPSAYMREHNQLNGWSSDENDWNEKLYP
  VWKRGDMRWKNSWKGGRVQAVLTSDSPALVGSNITFAVNLIFPRCQKEDANGNIVYEKNC
  RNEAGLSADPYVYNWTAWSEDSDGENGTGQSHHNVFPDGKPFPHHPGWRRWNFIYVFHTL
  GQYFQKLGRCSVRVSVNTANVTLGPQLMEVTVYRRHGRAYVPIAQVKDVYVVTDQIPVFV
  TMFQKNDRNSSDETFLKDLPIMFDVLIHDPSHFLNYSTINYKWSFGDNTGLFVSTNHTVN
  HTYVLNGTFSLNLTVKAAAPGPCPPPPPPPRPSKPTPSLATTLKSYDSNTPGPAGDNPLE
  LSRIPDENCQINRYGHFQATITIVEGILEVNIIQMTDVLMPVPWPESSLIDFVVTCQGSI
  PTEVCTIISDPTCEITQNTVCSPVDVDEMCLLTVRRTFNGSGTYCVNLTLGDDTSLALTS
  TLISVPDRDPASPLRMANSALISVGCLAIFVTVISLLVYKKHKEYNPIENSPGNVVRSKG
  LSVFLNRAKAVFFPGNQEKDPLLKNQEFKGVS
• Function: Could be a melanogenic enzyme.
• Tissue Specificity: Widely expressed, but very low expression, if any, in the brain . Expressed in the epidermis with higher levels in melanocytes compared with keratinocytes and Langerhans cells (at protein level) . Expressed in peripheral blood, but not bone marrow mononuclear cells . Expressed in tissue macrophages, including liver Kuppfer cells and lung alveolar macrophages, in podocytes and in some cells of the ciliary body of the eye (at protein level) . May be overexpressed in various cancers, including melanoma and glioblastoma multiforme .
• Reactome Pathway: PTK6 promotes HIF1A stabilization (R-HSA-8857538)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis, primary localized cutaneous, 3	DISZ2WA2	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[16]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[17]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[18]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[19]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[20]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[7]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[21]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[22]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[24]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[25]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane glycoprotein NMB (GPNMB).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[15]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Transmembrane glycoprotein NMB (GPNMB).	[32]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Transmembrane glycoprotein NMB (GPNMB).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Transmembrane glycoprotein NMB (GPNMB).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transmembrane glycoprotein NMB (GPNMB).	[27]

References

• [1] Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans. Am J Hum Genet. 2018 Feb 1;102(2):219-232. doi: 10.1016/j.ajhg.2017.12.012. Epub 2018 Jan 11.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [17] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [18] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [19] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [20] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [21] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [22] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [23] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [26] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [27] 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.
• [28] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [29] 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.
• [30] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [31] 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.
• [32] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [33] Cancer-related proteins in serum are altered in workers occupationally exposed to polycyclic aromatic hydrocarbons: a cross-sectional study. Carcinogenesis. 2019 Jul 6;40(6):771-781. doi: 10.1093/carcin/bgz022.