Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTRYF9Y)

• DOT Name: Tropomodulin-1 (TMOD1)
• Synonyms: Erythrocyte tropomodulin; E-Tmod
• Gene Name: TMOD1
• Related Disease:
  Advanced cancer
  Anaplastic large cell lymphoma
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Dilated cardiomyopathy 1A
  Esophageal adenocarcinoma
  Oral cancer
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Prostate cancer
  Prostate neoplasm
  Transitional cell carcinoma
  Acute myelogenous leukaemia
  Neoplasm
  Neuroblastoma
• UniProt ID: TMOD1_HUMAN
• PDB ID: 4PKG; 4PKH; 4PKI; 4Z8G; 4Z94; 8F8T
• Pfam ID: PF03250
• Sequence:
  MSYRRELEKYRDLDEDEILGALTEEELRTLENELDELDPDNALLPAGLRQKDQTTKAPTG
  PFKREELLDHLEKQAKEFKDREDLVPYTGEKRGKVWVPKQKPLDPVLESVTLEPELEEAL
  ANASDAELCDIAAILGMHTLMSNQQYYQALSSSSIMNKEGLNSVIKPTQYKPVPDEEPNS
  TDVEETLERIKNNDPKLEEVNLNNIRNIPIPTLKAYAEALKENSYVKKFSIVGTRSNDPV
  AYALAEMLKENKVLKTLNVESNFISGAGILRLVEALPYNTSLVEMKIDNQSQPLGNKVEM
  EIVSMLEKNATLLKFGYHFTQQGPRLRASNAMMNNNDLVRKRRLADLTGPIIPKCRSGV
• Function: Blocks the elongation and depolymerization of the actin filaments at the pointed end. The Tmod/TM complex contributes to the formation of the short actin protofilament, which in turn defines the geometry of the membrane skeleton. May play an important role in regulating the organization of actin filaments by preferentially binding to a specific tropomyosin isoform at its N-terminus.
• Tissue Specificity: Highly expressed in the erythrocyte, heart and skeletal muscle.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[2]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[5]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[3]
Oral cancer	DISLD42D	Strong	Altered Expression	[6]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[4]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tropomodulin-1 (TMOD1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tropomodulin-1 (TMOD1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tropomodulin-1 (TMOD1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tropomodulin-1 (TMOD1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tropomodulin-1 (TMOD1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tropomodulin-1 (TMOD1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tropomodulin-1 (TMOD1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tropomodulin-1 (TMOD1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tropomodulin-1 (TMOD1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Tropomodulin-1 (TMOD1).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tropomodulin-1 (TMOD1).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Tropomodulin-1 (TMOD1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tropomodulin-1 (TMOD1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tropomodulin-1 (TMOD1).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Tropomodulin-1 (TMOD1).	[25]

References

• [1] Targeted regulation of miR-17-5p on TMOD1 promotes the development of cardia cancer.Eur Rev Med Pharmacol Sci. 2019 Jul;23(14):6170-6178. doi: 10.26355/eurrev_201907_18430.
• [2] Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma.Blood. 2012 Aug 9;120(6):1274-81. doi: 10.1182/blood-2012-01-405555. Epub 2012 Jun 27.
• [3] Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.Lancet Oncol. 2016 Oct;17(10):1363-1373. doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.
• [4] Tropomodulin 1 expression driven by NF-B enhances breast cancer growth.Cancer Res. 2015 Jan 1;75(1):62-72. doi: 10.1158/0008-5472.CAN-13-3455. Epub 2014 Nov 14.
• [5] Localization of the binding interface between leiomodin-2 and -tropomyosin.Biochim Biophys Acta. 2016 May;1864(5):523-30. doi: 10.1016/j.bbapap.2016.02.009. Epub 2016 Feb 9.
• [6] Overexpression of TMOD1 is associated with enhanced regional lymph node metastasis in human oral cancer.Int J Oncol. 2016 Feb;48(2):607-12. doi: 10.3892/ijo.2015.3305. Epub 2015 Dec 22.
• [7] Global analysis of differentially expressed genes in androgen-independent prostate cancer.Prostate Cancer Prostatic Dis. 2007;10(2):167-74. doi: 10.1038/sj.pcan.4500933. Epub 2007 Jan 2.
• [8] Alterations in tropomyosin isoform expression in human transitional cell carcinoma of the urinary bladder.Int J Cancer. 2004 Jun 20;110(3):368-73. doi: 10.1002/ijc.20151.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Favorable prognostic role of tropomodulins in neuroblastoma.Oncotarget. 2018 Jun 5;9(43):27092-27103. doi: 10.18632/oncotarget.25491. eCollection 2018 Jun 5.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [22] 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.
• [23] 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.
• [24] 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.
• [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.