Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL6EOS1)

• DOT Name: T-complex protein 1 subunit gamma (CCT3)
• Synonyms: TCP-1-gamma; CCT-gamma; hTRiC5
• Gene Name: CCT3
• Related Disease:
  Adult glioblastoma
  Myotonic syndrome
  Adenocarcinoma
  Breast cancer
  Breast carcinoma
  Friedreich ataxia 1
  Glioblastoma multiforme
  Hepatocellular carcinoma
  HIV infectious disease
  Myotonic dystrophy type 2
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Triple negative breast cancer
  Thyroid gland papillary carcinoma
  Advanced cancer
  Colorectal carcinoma
  Rheumatoid arthritis
• UniProt ID: TCPG_HUMAN
• PDB ID: 6NR8 ; 6NR9 ; 6NRA ; 6NRB ; 6NRC ; 6NRD ; 6QB8 ; 7LUM ; 7LUP ; 7NVL ; 7NVM ; 7NVN ; 7NVO ; 7TRG ; 7TTN ; 7TTT ; 7TUB ; 7WU7 ; 7WZ3 ; 7X0A ; 7X0S ; 7X0V ; 7X3J ; 7X3U ; 7X6Q ; 7X7Y ; 8SFE ; 8SFF ; 8SG8 ; 8SG9 ; 8SGC ; 8SGL ; 8SGQ ; 8SH9 ; 8SHA ; 8SHD ; 8SHE ; 8SHF ; 8SHG ; 8SHL ; 8SHN ; 8SHO ; 8SHP ; 8SHQ ; 8SHT
• Pfam ID: PF00118
• Sequence:
  MMGHRPVLVLSQNTKRESGRKVQSGNINAAKTIADIIRTCLGPKSMMKMLLDPMGGIVMT
  NDGNAILREIQVQHPAAKSMIEISRTQDEEVGDGTTSVIILAGEMLSVAEHFLEQQMHPT
  VVISAYRKALDDMISTLKKISIPVDISDSDMMLNIINSSITTKAISRWSSLACNIALDAV
  KMVQFEENGRKEIDIKKYARVEKIPGGIIEDSCVLRGVMINKDVTHPRMRRYIKNPRIVL
  LDSSLEYKKGESQTDIEITREEDFTRILQMEEEYIQQLCEDIIQLKPDVVITEKGISDLA
  QHYLMRANITAIRRVRKTDNNRIARACGARIVSRPEELREDDVGTGAGLLEIKKIGDEYF
  TFITDCKDPKACTILLRGASKEILSEVERNLQDAMQVCRNVLLDPQLVPGGGASEMAVAH
  ALTEKSKAMTGVEQWPYRAVAQALEVIPRTLIQNCGASTIRLLTSLRAKHTQENCETWGV
  NGETGTLVDMKELGIWEPLAVKLQTYKTAVETAVLLLRIDDIVSGHKKKGDDQSRQGGAP
  DAGQE
• Function: Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance. As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia. The TRiC complex plays a role in the folding of actin and tubulin (Probable).
• Reactome Pathway:
  Formation of tubulin folding intermediates by CCT/TriC (R-HSA-389960)
  Folding of actin by CCT/TriC (R-HSA-390450)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  Prefoldin mediated transfer of substrate to CCT/TriC (R-HSA-389957)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Myotonic syndrome	DISPCJM5	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Friedreich ataxia 1	DIS285GE	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Myotonic dystrophy type 2	DIS5ZWF1	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[9]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[10]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[11]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of T-complex protein 1 subunit gamma (CCT3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of T-complex protein 1 subunit gamma (CCT3).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of T-complex protein 1 subunit gamma (CCT3).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of T-complex protein 1 subunit gamma (CCT3).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of T-complex protein 1 subunit gamma (CCT3).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-complex protein 1 subunit gamma (CCT3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of T-complex protein 1 subunit gamma (CCT3).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of T-complex protein 1 subunit gamma (CCT3).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of T-complex protein 1 subunit gamma (CCT3).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of T-complex protein 1 subunit gamma (CCT3).	[21]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of T-complex protein 1 subunit gamma (CCT3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of T-complex protein 1 subunit gamma (CCT3).	[28]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of T-complex protein 1 subunit gamma (CCT3).	[29]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of T-complex protein 1 subunit gamma (CCT3).	[23]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of T-complex protein 1 subunit gamma (CCT3).	[24]

References

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• [2] Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2.Eur J Histochem. 2006 Jul-Sep;50(3):177-82.
• [3] Improved Survival Seen for Some with Pancreatic Cancer.Cancer Discov. 2018 Sep;8(9):OF1. doi: 10.1158/2159-8290.CD-NB2018-105. Epub 2018 Aug 13.
• [4] Region-specific glucocorticoid receptor promoter methylation has both positive and negative prognostic value in patients with estrogen receptor-positive breast cancer.Clin Epigenetics. 2019 Nov 1;11(1):155. doi: 10.1186/s13148-019-0750-x.
• [5] Non-B DNA conformations formed by long repeating tracts of myotonic dystrophy type 1, myotonic dystrophy type 2, and Friedreich's ataxia genes, not the sequences per se, promote mutagenesis in flanking regions.J Biol Chem. 2006 Aug 25;281(34):24531-43. doi: 10.1074/jbc.M603888200. Epub 2006 Jun 21.
• [6] Clinical and prognostic value of chaperonin containing T-complex 1 subunit 3 in hepatocellular carcinoma: A Study based on microarray and RNA-sequencing with 4272 cases.Pathol Res Pract. 2019 Jan;215(1):177-194. doi: 10.1016/j.prp.2018.11.006. Epub 2018 Nov 10.
• [7] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [8] Unprecedented hydrophobic stabilizations from a reverse wobble TT mispair in DNA minidumbbell.J Biomol Struct Dyn. 2020 Apr;38(7):1946-1953. doi: 10.1080/07391102.2019.1621211. Epub 2019 May 30.
• [9] Randomised Phase II Feasibility Trial of Image-guided External Beam Radiotherapy With or Without High Dose Rate Brachytherapy Boost in Men with Intermediate-risk Prostate Cancer (CCTG PR15/ NCT01982786).Clin Oncol (R Coll Radiol). 2018 Sep;30(9):527-533. doi: 10.1016/j.clon.2018.05.007. Epub 2018 Jun 11.
• [10] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [11] Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.Breast Cancer Res Treat. 2016 May;157(1):109-16. doi: 10.1007/s10549-016-3812-1. Epub 2016 Apr 26.
• [12] Suppression of CCT3 inhibits malignant proliferation of human papillary thyroid carcinoma cell.Oncol Lett. 2018 Jun;15(6):9202-9208. doi: 10.3892/ol.2018.8496. Epub 2018 Apr 13.
• [13] Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells.Cancer Lett. 2016 Mar 1;372(1):101-9. doi: 10.1016/j.canlet.2015.12.029. Epub 2015 Dec 29.
• [14] Discovery and scoring of protein interaction subnetworks discriminative of late stage human colon cancer.Mol Cell Proteomics. 2009 Apr;8(4):827-45. doi: 10.1074/mcp.M800428-MCP200. Epub 2008 Dec 19.
• [15] Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.Neuromuscul Disord. 2015 Feb;25(2):149-52. doi: 10.1016/j.nmd.2014.09.009. Epub 2014 Sep 28.
• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] 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.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [21] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [22] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [23] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [24] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [25] 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.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] 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.
• [28] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [29] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.