Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8PBOAR)

• DOT Name: Troponin T, slow skeletal muscle (TNNT1)
• Synonyms: TnTs; Slow skeletal muscle troponin T; sTnT
• Gene Name: TNNT1
• Related Disease:
  Nemaline myopathy 5
  Breast cancer
  Breast carcinoma
  Fabry disease
  Familial hypercholesterolemia
  Familial multiple trichoepithelioma
  Friedreich's ataxia
  Hypercholesterolemia, familial, 1
  Myopathy
  Neoplasm
  Psoriasis
  Vitamin D deficiency
  Colorectal carcinoma
  Ewing sarcoma
  Metastatic malignant neoplasm
  Neuromuscular disease
  Rhabdomyosarcoma
  Triple negative breast cancer
  Chronic obstructive pulmonary disease
  Colon adenocarcinoma
  Coronary atherosclerosis
  Coronary heart disease
  GNE myopathy
  Nemaline myopathy
  Nemaline myopathy 5C, autosomal dominant
• UniProt ID: TNNT1_HUMAN
• Pfam ID: PF00992
• Sequence:
  MSDTEEQEYEEEQPEEEAAEEEEEAPEEPEPVAEPEEERPKPSRPVVPPLIPPKIPEGER
  VDFDDIHRKRMEKDLLELQTLIDVHFEQRKKEEEELVALKERIERRRSERAEQQRFRTEK
  ERERQAKLAEEKMRKEEEEAKKRAEDDAKKKKVLSNMGAHFGGYLVKAEQKRGKRQTGRE
  MKVRILSERKKPLDIDYMGEEQLRARSAWLPPSQPSCPAREKAQELSDWIHQLESEKFDL
  MAKLKQQKYEINVLYNRISHAQKFRKGAGKGRVGGRWK
• Function: Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nemaline myopathy 5	DISNFIVZ	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Fabry disease	DISUUQJF	Strong	Biomarker	[3]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[4]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[5]
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[3]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[4]
Myopathy	DISOWG27	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Psoriasis	DIS59VMN	Strong	Biomarker	[8]
Vitamin D deficiency	DISAWKYI	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[10]
Ewing sarcoma	DISQYLV3	moderate	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[12]
Neuromuscular disease	DISQTIJZ	moderate	Biomarker	[10]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[11]
Triple negative breast cancer	DISAMG6N	moderate	Genetic Variation	[13]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[14]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[14]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[15]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[15]
GNE myopathy	DIS73X4W	Limited	Biomarker	[16]
Nemaline myopathy	DIS5IYLY	Limited	Autosomal dominant	[1]
Nemaline myopathy 5C, autosomal dominant	DIS4A084	Limited	Autosomal dominant	[17]

21 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 Troponin T, slow skeletal muscle (TNNT1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Troponin T, slow skeletal muscle (TNNT1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Troponin T, slow skeletal muscle (TNNT1).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Troponin T, slow skeletal muscle (TNNT1).	[27]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[28]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[29]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[20]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[30]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Troponin T, slow skeletal muscle (TNNT1).	[35]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Troponin T, slow skeletal muscle (TNNT1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Troponin T, slow skeletal muscle (TNNT1).	[32]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] TNNT1 facilitates proliferation of breast cancer cells by promoting G(1)/S phase transition.Life Sci. 2018 Sep 1;208:161-166. doi: 10.1016/j.lfs.2018.07.034. Epub 2018 Jul 19.
• [3] Value of cardiac biomarker measurement in the differential diagnosis of infiltrative cardiomyopathy patients with preserved left ventricular systolic function.J Thorac Dis. 2018 Aug;10(8):4966-4975. doi: 10.21037/jtd.2018.07.56.
• [4] Epigenetic and genetic variations at the TNNT1 gene locus are associated with HDL-C levels and coronary artery disease.Epigenomics. 2016 Mar;8(3):359-71. doi: 10.2217/epi.15.120. Epub 2016 Mar 7.
• [5] Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium.PLoS One. 2015 Jul 1;10(7):e0130909. doi: 10.1371/journal.pone.0130909. eCollection 2015.
• [6] The loss of slow skeletal muscle isoform of troponin T in spindle intrafusal fibres explains the pathophysiology of Amish nemaline myopathy.J Physiol. 2019 Aug;597(15):3999-4012. doi: 10.1113/JP278119. Epub 2019 Jul 3.
• [7] Platinum salts in the treatment of BRCA-associated breast cancer: A true targeted chemotherapy?.Crit Rev Oncol Hematol. 2019 Mar;135:66-75. doi: 10.1016/j.critrevonc.2019.01.016. Epub 2019 Jan 30.
• [8] Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis.Clin Drug Investig. 2017 Aug;37(8):775-785. doi: 10.1007/s40261-017-0533-0.
• [9] Disrupted expression of genes essential for skeletal muscle fibre integrity and energy metabolism in Vitamin D deficient rats.J Steroid Biochem Mol Biol. 2020 Mar;197:105525. doi: 10.1016/j.jsbmb.2019.105525. Epub 2019 Nov 6.
• [10] TNNT1, negatively regulated by miR-873, promotes the progression of colorectal cancer.J Gene Med. 2020 Feb;22(2):e3152. doi: 10.1002/jgm.3152. Epub 2019 Dec 23.
• [11] Artificial neural network inference (ANNI): a study on gene-gene interaction for biomarkers in childhood sarcomas.PLoS One. 2014 Jul 15;9(7):e102483. doi: 10.1371/journal.pone.0102483. eCollection 2014.
• [12] Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer.Ann Surg. 2021 Feb 1;273(2):341-349. doi: 10.1097/SLA.0000000000003284.
• [13] Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.Nat Med. 2018 May;24(5):628-637. doi: 10.1038/s41591-018-0009-7. Epub 2018 Apr 30.
• [14] TNNT1, a prognostic indicator in colon adenocarcinoma, regulates cell behaviors and mediates EMT process.Biosci Biotechnol Biochem. 2020 Jan;84(1):111-117. doi: 10.1080/09168451.2019.1664891. Epub 2019 Sep 12.
• [15] Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.Circulation. 2018 Aug 21;138(8):770-781. doi: 10.1161/CIRCULATIONAHA.117.032318.
• [16] 'Amish Nemaline Myopathy' in 2 Italian siblings harbouring a novel homozygous mutation in Troponin-I gene.Neuromuscul Disord. 2019 Oct;29(10):766-770. doi: 10.1016/j.nmd.2019.09.005. Epub 2019 Sep 6.
• [17] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [18] 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.
• [19] 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.
• [20] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 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.
• [23] 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.
• [24] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [25] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [26] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [27] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [28] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [29] Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice. Br J Pharmacol. 2019 May;176(10):1568-1584. doi: 10.1111/bph.14460. Epub 2018 Sep 9.
• [30] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [31] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.