Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKNJDH7)

• DOT Name: Osteopetrosis-associated transmembrane protein 1 (OSTM1)
• Synonyms: Chloride channel 7 beta subunit
• Gene Name: OSTM1
• Related Disease:
  Autosomal recessive osteopetrosis 5
  Bone disease
  Hamartoma
  Major depressive disorder
  Type-1/2 diabetes
  Infantile osteopetrosis with neuroaxonal dysplasia
  Infantile malignant osteopetrosis
  Osteoporosis
  Lysosomal storage disease
  Osteopetrosis
• UniProt ID: OSTM1_HUMAN
• PDB ID: 7BXU; 7CQ5; 7CQ6; 7CQ7; 7JM7
• Pfam ID: PF09777
• Sequence:
  MEPGPTAAQRRCSLPPWLPLGLLLWSGLALGALPFGSSPHRVFHDLLSEQQLLEVEDLSL
  SLLQGGGLGPLSLPPDLPDLDPECRELLLDFANSSAELTGCLVRSARPVRLCQTCYPLFQ
  QVVSKMDNISRAAGNTSESQSCARSLLMADRMQIVVILSEFFNTTWQEANCANCLTNNSE
  ELSNSTVYFLNLFNHTLTCFEHNLQGNAHSLLQTKNYSEVCKNCREAYKTLSSLYSEMQK
  MNELENKAEPGTHLCIDVEDAMNITRKLWSRTFNCSVPCSDTVPVIAVSVFILFLPVVFY
  LSSFLHSEQKKRKLILPKRLKSSTSFANIQENSN
• Function: Required for osteoclast and melanocyte maturation and function.
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive osteopetrosis 5	DISF89YZ	Strong	Autosomal recessive	[1]
Bone disease	DISE1F82	Strong	Biomarker	[2]
Hamartoma	DIS0I87H	Strong	Genetic Variation	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]
Infantile osteopetrosis with neuroaxonal dysplasia	DIS0NIDC	Supportive	Autosomal recessive	[5]
Infantile malignant osteopetrosis	DIS8C3LZ	Disputed	Biomarker	[6]
Osteoporosis	DISF2JE0	Disputed	Biomarker	[7]
Lysosomal storage disease	DIS6QM6U	Limited	Genetic Variation	[3]
Osteopetrosis	DIS7GHNM	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Apilimod dimesylate	DM4N2O0	Phase 2	Osteopetrosis-associated transmembrane protein 1 (OSTM1) affects the response to substance of Apilimod dimesylate.	[27]

17 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 Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[14]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[15]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[16]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[25]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Osteopetrosis-associated transmembrane protein 1 (OSTM1).	[22]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Effect of bergenin on RANKL-induced osteoclast differentiation in the presence of methylglyoxal.Toxicol In Vitro. 2019 Dec;61:104613. doi: 10.1016/j.tiv.2019.104613. Epub 2019 Jul 29.
• [3] A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.Dis Model Mech. 2014 Jan;7(1):119-28. doi: 10.1242/dmm.012500. Epub 2013 Oct 23.
• [4] Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank.Transl Psychiatry. 2017 Nov 30;7(11):1263. doi: 10.1038/s41398-017-0010-9.
• [5] Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1. Bone. 2013 Aug;55(2):292-7. doi: 10.1016/j.bone.2013.04.007. Epub 2013 Apr 17.
• [6] SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.J Bone Miner Res. 2013 May;28(5):1041-9. doi: 10.1002/jbmr.1849.
• [7] Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation.J Bone Miner Res. 2018 May;33(5):888-898. doi: 10.1002/jbmr.3378. Epub 2018 Feb 14.
• [8] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015 Feb 3;328:102-11. doi: 10.1016/j.tox.2014.12.018. Epub 2014 Dec 18.
• [13] 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.
• [14] 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.
• [15] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [16] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [17] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [18] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [19] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] 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.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [26] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [27] Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768-1778. doi: 10.1182/blood-2016-09-736892. Epub 2017 Jan 19.