Details of Drug Off-Target (DOT)

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

• DOT Name: Tropomodulin-3 (TMOD3)
• Synonyms: Ubiquitous tropomodulin; U-Tmod
• Gene Name: TMOD3
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Disorder of orbital region
  Endometriosis
  Liver cancer
  Transitional cell carcinoma
• UniProt ID: TMOD3_HUMAN
• Pfam ID: PF03250
• Sequence:
  MALPFRKDLEKYKDLDEDELLGNLSETELKQLETVLDDLDPENALLPAGFRQKNQTSKST
  TGPFDREHLLSYLEKEALEHKDREDYVPYTGEKKGKIFIPKQKPVQTFTEEKVSLDPELE
  EALTSASDTELCDLAAILGMHNLITNTKFCNIMGSSNGVDQEHFSNVVKGEKILPVFDEP
  PNPTNVEESLKRTKENDAHLVEVNLNNIKNIPIPTLKDFAKALETNTHVKCFSLAATRSN
  DPVATAFAEMLKVNKTLKSLNVESNFITGVGILALIDALRDNETLAELKIDNQRQQLGTA
  VELEMAKMLEENTNILKFGYQFTQQGPRTRAANAITKNNDLVRKRRVEGDHQ
• 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.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  RHOBTB2 GTPase cycle (R-HSA-9013418)
  RND3 GTPase cycle (R-HSA-9696264)
  Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[2]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[3]
Endometriosis	DISX1AG8	Strong	Biomarker	[4]
Liver cancer	DISDE4BI	Strong	Altered Expression	[2]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tropomodulin-3 (TMOD3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tropomodulin-3 (TMOD3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tropomodulin-3 (TMOD3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tropomodulin-3 (TMOD3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Tropomodulin-3 (TMOD3).	[10]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Tropomodulin-3 (TMOD3).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tropomodulin-3 (TMOD3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tropomodulin-3 (TMOD3).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Tropomodulin-3 (TMOD3).	[15]

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 affects the phosphorylation of Tropomodulin-3 (TMOD3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tropomodulin-3 (TMOD3).	[16]

References

• [1] Tropomodulin 3 modulates EGFR-PI3K-AKT signaling to drive hepatocellular carcinoma metastasis.Mol Carcinog. 2019 Oct;58(10):1897-1907. doi: 10.1002/mc.23083. Epub 2019 Jul 16.
• [2] Tropomodulin3 promotes liver cancer progression by activating the MAPK/ERK signaling pathway.Oncol Rep. 2019 May;41(5):3060-3068. doi: 10.3892/or.2019.7052. Epub 2019 Mar 7.
• [3] MicroRNA-145 Regulates Pathological Retinal Angiogenesis by Suppression of TMOD3.Mol Ther Nucleic Acids. 2019 Jun 7;16:335-347. doi: 10.1016/j.omtn.2019.03.001. Epub 2019 Mar 21.
• [4] Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-Mild Endometriosis.Reprod Sci. 2017 Mar;24(3):413-420. doi: 10.1177/1933719116657190. Epub 2016 Sep 27.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [14] 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.
• [15] 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.
• [16] 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.