Details of Drug Off-Target (DOT)

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

• DOT Name: Tetratricopeptide repeat protein 4 (TTC4)
• Synonyms: TPR repeat protein 4
• Gene Name: TTC4
• Related Disease:
  Glioma
  Type-1 diabetes
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Breast neoplasm
  Childhood acute lymphoblastic leukemia
  Crigler-najjar syndrome type 1
  Glioblastoma multiforme
  Gliosarcoma
  Neoplasm
  Melanoma
  Cutaneous melanoma
  Metastatic malignant neoplasm
  Type-1/2 diabetes
• UniProt ID: TTC4_HUMAN
• PDB ID: 6HFO
• Pfam ID: PF18972
• Sequence:
  MEQPGQDPTSDDVMDSFLEKFQSQPYRGGFHEDQWEKEFEKVPLFMSRAPSEIDPRENPD
  LACLQSIIFDEERSPEEQAKTYKDEGNDYFKEKDYKKAVISYTEGLKKKCADPDLNAVLY
  TNRAAAQYYLGNFRSALNDVTAARKLKPCHLKAIIRGALCHLELKHFAEAVNWCDEGLQI
  DAKEKKLLEMRAKADKLKRIEQRDVRKANLKEKKERNQNEALLQAIKARNIRLSEAACED
  EDSASEGLGELFLDGLSTENPHGARLSLDGQGRLSWPVLFLYPEYAQSDFISAFHEDSRF
  IDHLMVMFGETPSWDLEQKYCPDNLEVYFEDEDRAELYRVPAKSTLLQVLQHQRYFVKAL
  TPAFLVCVGSSPFCKNFLRGRKVYQIR
• Function: May act as a co-chaperone for HSP90AB1. Promotes Sendai virus (SeV)-induced host cell innate immune responses.
• Tissue Specificity: Highly expressed in proliferating tissue and tumor cell lines but not in normal cell lines.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Crigler-najjar syndrome type 1	DISBEAZY	Strong	Genetic Variation	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[8]
Gliosarcoma	DIS985MG	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[10]
Cutaneous melanoma	DIS3MMH9	Limited	Genetic Variation	[11]
Metastatic malignant neoplasm	DIS86UK6	Limited	Genetic Variation	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[12]

3 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 Tetratricopeptide repeat protein 4 (TTC4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tetratricopeptide repeat protein 4 (TTC4).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tetratricopeptide repeat protein 4 (TTC4).	[17]

2 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 Tetratricopeptide repeat protein 4 (TTC4).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Tetratricopeptide repeat protein 4 (TTC4).	[15]

References

• [1] Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model.J Neurooncol. 2013 Aug;114(1):33-42. doi: 10.1007/s11060-013-1158-7. Epub 2013 May 22.
• [2] Thymically-derived Foxp3+ regulatory T cells are the primary regulators of type 1 diabetes in the non-obese diabetic mouse model.PLoS One. 2019 Oct 24;14(10):e0217728. doi: 10.1371/journal.pone.0217728. eCollection 2019.
• [3] Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.Cancer. 2018 Dec 1;124(23):4538-4547. doi: 10.1002/cncr.31758. Epub 2018 Oct 10.
• [4] The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: a Children's Oncology Group study.Pediatr Blood Cancer. 2010 Sep;55(3):414-20. doi: 10.1002/pbc.22511.
• [5] Neuromyelitis optica spectrum disorder after treatment with pembrolizumab.Mult Scler Relat Disord. 2020 Jan;37:101447. doi: 10.1016/j.msard.2019.101447. Epub 2019 Oct 14.
• [6] Genomic structure of the human tetratricopeptide repeat-containing gene, TTC4, from chromosome region 1p31 and mutation analysis in breast cancers.Int J Mol Med. 2000 Feb;5(2):197-200.
• [7] Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.J Gastroenterol Hepatol. 2020 Apr;35(4):530-543. doi: 10.1111/jgh.14853. Epub 2019 Oct 24.
• [8] A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma.Front Neurol. 2018 Dec 17;9:1087. doi: 10.3389/fneur.2018.01087. eCollection 2018.
• [9] A rat glioma model, CNS-1, with invasive characteristics similar to those of human gliomas: a comparison to 9L gliosarcoma.J Neurooncol. 1994;22(3):191-200. doi: 10.1007/BF01052919.
• [10] The human TPR protein TTC4 is a putative Hsp90 co-chaperone which interacts with CDC6 and shows alterations in transformed cells.PLoS One. 2008 Mar 5;3(3):e0001737. doi: 10.1371/journal.pone.0001737.
• [11] TTC4, a novel candidate tumor suppressor gene at 1p31 is often mutated in malignant melanoma of the skin.Oncogene. 2000 Nov 23;19(50):5817-20. doi: 10.1038/sj.onc.1203961.
• [12] Peripherally induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model.Eur J Immunol. 2018 Jul;48(7):1211-1216. doi: 10.1002/eji.201847498. Epub 2018 Apr 25.
• [13] 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.
• [14] 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.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] 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.
• [17] 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.