Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHB78ZQ)

• DOT Name: Unconventional myosin-X (MYO10)
• Synonyms: Unconventional myosin-10
• Gene Name: MYO10
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Breast cancer
  Breast carcinoma
  Cholelithiasis
  Colorectal carcinoma
  Lung squamous cell carcinoma
  Major depressive disorder
  Non-small-cell lung cancer
  Advanced cancer
  Pancreatic ductal carcinoma
  Melanoma
  Neoplasm
  Neuroblastoma
• UniProt ID: MYO10_HUMAN
• PDB ID: 2LW9; 3AU4; 3AU5; 3PZD; 5I0H; 5I0I; 5KG8
• Pfam ID: PF00373 ; PF00612 ; PF16735 ; PF00063 ; PF00784 ; PF00169 ; PF00788 ; PF18597
• Sequence:
  MDNFFTEGTRVWLRENGQHFPSTVNSCAEGIVVFRTDYGQVFTYKQSTITHQKVTAMHPT
  NEEGVDDMASLTELHGGSIMYNLFQRYKRNQIYTYIGSILASVNPYQPIAGLYEPATMEQ
  YSRRHLGELPPHIFAIANECYRCLWKRHDNQCILISGESGAGKTESTKLILKFLSVISQQ
  SLELSLKEKTSCVERAILESSPIMEAFGNAKTVYNNNSSRFGKFVQLNICQKGNIQGGRI
  VDYLLEKNRVVRQNPGERNYHIFYALLAGLEHEEREEFYLSTPENYHYLNQSGCVEDKTI
  SDQESFREVITAMDVMQFSKEEVREVSRLLAGILHLGNIEFITAGGAQVSFKTALGRSAE
  LLGLDPTQLTDALTQRSMFLRGEEILTPLNVQQAVDSRDSLAMALYACCFEWVIKKINSR
  IKGNEDFKSIGILDIFGFENFEVNHFEQFNINYANEKLQEYFNKHIFSLEQLEYSREGLV
  WEDIDWIDNGECLDLIEKKLGLLALINEESHFPQATDSTLLEKLHSQHANNHFYVKPRVA
  VNNFGVKHYAGEVQYDVRGILEKNRDTFRDDLLNLLRESRFDFIYDLFEHVSSRNNQDTL
  KCGSKHRRPTVSSQFKDSLHSLMATLSSSNPFFVRCIKPNMQKMPDQFDQAVVLNQLRYS
  GMLETVRIRKAGYAVRRPFQDFYKRYKVLMRNLALPEDVRGKCTSLLQLYDASNSEWQLG
  KTKVFLRESLEQKLEKRREEEVSHAAMVIRAHVLGFLARKQYRKVLYCVVIIQKNYRAFL
  LRRRFLHLKKAAIVFQKQLRGQIARRVYRQLLAEKREQEEKKKQEEEEKKKREEEERERE
  RERREAELRAQQEEETRKQQELEALQKSQKEAELTRELEKQKENKQVEEILRLEKEIEDL
  QRMKEQQELSLTEASLQKLQERRDQELRRLEEEACRAAQEFLESLNFDEIDECVRNIERS
  LSVGSEFSSELAESACEEKPNFNFSQPYPEEEVDEGFEADDDAFKDSPNPSEHGHSDQRT
  SGIRTSDDSSEEDPYMNDTVVPTSPSADSTVLLAPSVQDSGSLHNSSSGESTYCMPQNAG
  DLPSPDGDYDYDQDDYEDGAITSGSSVTFSNSYGSQWSPDYRCSVGTYNSSGAYRFSSEG
  AQSSFEDSEEDFDSRFDTDDELSYRRDSVYSCVTLPYFHSFLYMKGGLMNSWKRRWCVLK
  DETFLWFRSKQEALKQGWLHKKGGGSSTLSRRNWKKRWFVLRQSKLMYFENDSEEKLKGT
  VEVRTAKEIIDNTTKENGIDIIMADRTFHLIAESPEDASQWFSVLSQVHASTDQEIQEMH
  DEQANPQNAVGTLDVGLIDSVCASDSPDRPNSFVIITANRVLHCNADTPEEMHHWITLLQ
  RSKGDTRVEGQEFIVRGWLHKEVKNSPKMSSLKLKKRWFVLTHNSLDYYKSSEKNALKLG
  TLVLNSLCSVVPPDEKIFKETGYWNVTVYGRKHCYRLYTKLLNEATRWSSAIQNVTDTKA
  PIDTPTQQLIQDIKENCLNSDVVEQIYKRNPILRYTHHPLHSPLLPLPYGDINLNLLKDK
  GYTTLQDEAIKIFNSLQQLESMSDPIPIIQGILQTGHDLRPLRDELYCQLIKQTNKVPHP
  GSVGNLYSWQILTCLSCTFLPSRGILKYLKFHLKRIREQFPGSEMEKYALFTYESLKKTK
  CREFVPSRDEIEALIHRQEMTSTVYCHGGGSCKITINSHTTAGEVVEKLIRGLAMEDSRN
  MFALFEYNGHVDKAIESRTVVADVLAKFEKLAATSEVGDLPWKFYFKLYCFLDTDNVPKD
  SVEFAFMFEQAHEAVIHGHHPAPEENLQVLAALRLQYLQGDYTLHAAIPPLEEVYSLQRL
  KARISQSTKTFTPCERLEKRRTSFLEGTLRRSFRTGSVVRQKVEEEQMLDMWIKEEVSSA
  RASIIDKWRKFQGMNQEQAMAKYMALIKEWPGYGSTLFDVECKEGGFPQELWLGVSADAV
  SVYKRGEGRPLEVFQYEHILSFGAPLANTYKIVVDERELLFETSEVVDVAKLMKAYISMI
  VKKRYSTTRSASSQGSSR
• Function: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. MYO10 binds to actin filaments and actin bundles and functions as a plus end-directed motor. Moves with higher velocity and takes larger steps on actin bundles than on single actin filaments. The tail domain binds to membranous compartments containing phosphatidylinositol 3,4,5-trisphosphate or integrins, and mediates cargo transport along actin filaments. Regulates cell shape, cell spreading and cell adhesion. Stimulates the formation and elongation of filopodia. In hippocampal neurons it induces the formation of dendritic filopodia by trafficking the actin-remodeling protein VASP to the tips of filopodia, where it promotes actin elongation. Plays a role in formation of the podosome belt in osteoclasts; [Isoform Headless]: Functions as a dominant-negative regulator of isoform 1, suppressing its filopodia-inducing and axon outgrowth-promoting activities. In hippocampal neurons, it increases VASP retention in spine heads to induce spine formation and spine head expansion.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Fc gamma R-mediated phagocytosis (hsa04666)
  Motor proteins (hsa04814)
  Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway:
  Netrin-1 signaling (R-HSA-373752)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[4]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[8]
Melanoma	DIS1RRCY	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Unconventional myosin-X (MYO10) affects the response to substance of Mitomycin.	[28]
Chlorothiazide	DMLHESP	Approved	Unconventional myosin-X (MYO10) increases the Metabolic disorder ADR of Chlorothiazide.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Unconventional myosin-X (MYO10).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Unconventional myosin-X (MYO10).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Unconventional myosin-X (MYO10).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Unconventional myosin-X (MYO10).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Unconventional myosin-X (MYO10).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Unconventional myosin-X (MYO10).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Unconventional myosin-X (MYO10).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Unconventional myosin-X (MYO10).	[18]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Unconventional myosin-X (MYO10).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Unconventional myosin-X (MYO10).	[20]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of Unconventional myosin-X (MYO10).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Unconventional myosin-X (MYO10).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Unconventional myosin-X (MYO10).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Unconventional myosin-X (MYO10).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Unconventional myosin-X (MYO10).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Unconventional myosin-X (MYO10).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Unconventional myosin-X (MYO10).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Unconventional myosin-X (MYO10).	[27]

References

• [1] CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to enhance the transcriptional activity of -catenin/LEF1 complex via effects on chromatin remodeling.Mol Cancer. 2019 Oct 29;18(1):150. doi: 10.1186/s12943-019-1076-1.
• [2] MiR-340 suppresses cell migration and invasion by targeting MYO10 in breast cancer.Oncol Rep. 2016 Feb;35(2):709-16. doi: 10.3892/or.2015.4411. Epub 2015 Nov 12.
• [3] A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet. 2007 Aug;39(8):995-9. doi: 10.1038/ng2101. Epub 2007 Jul 15.
• [4] Protease activated receptor 2 mediates tryptase-induced cell migration through MYO10 in colorectal cancer.Am J Cancer Res. 2019 Sep 1;9(9):1995-2006. eCollection 2019.
• [5] Expression ratio of the TGF-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response.Sci Rep. 2018 Jun 22;8(1):9517. doi: 10.1038/s41598-018-27912-1.
• [6] Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies.Am J Psychiatry. 2013 Feb;170(2):207-17. doi: 10.1176/appi.ajp.2012.12020237.
• [7] NF-B-mediated miR-124 suppresses metastasis of non-small-cell lung cancer by targeting MYO10.Oncotarget. 2015 Apr 10;6(10):8244-54. doi: 10.18632/oncotarget.3135.
• [8] Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.J Clin Invest. 2014 Mar;124(3):1069-82. doi: 10.1172/JCI67280.
• [9] Myosin X is required for efficient melanoblast migration and melanoma initiation and metastasis.Sci Rep. 2018 Jul 11;8(1):10449. doi: 10.1038/s41598-018-28717-y.
• [10] miR-129 inhibits tumor growth and potentiates chemosensitivity of neuroblastoma by targeting MYO10.Biomed Pharmacother. 2018 Jul;103:1312-1318. doi: 10.1016/j.biopha.2018.04.153. Epub 2018 May 7.
• [11] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [12] 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.
• [13] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [20] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [21] Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.
• [26] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [27] 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.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [29] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.