Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCYWL5F)

• DOT Name: T-complex protein 1 subunit zeta (CCT6A)
• Synonyms: TCP-1-zeta; Acute morphine dependence-related protein 2; CCT-zeta-1; HTR3; Tcp20
• Gene Name: CCT6A
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Obsessive compulsive disorder
  Schizophrenia
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Tourette syndrome
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: TCPZ_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:
  MAAVKTLNPKAEVARAQAALAVNISAARGLQDVLRTNLGPKGTMKMLVSGAGDIKLTKDG
  NVLLHEMQIQHPTASLIAKVATAQDDITGDGTTSNVLIIGELLKQADLYISEGLHPRIIT
  EGFEAAKEKALQFLEEVKVSREMDRETLIDVARTSLRTKVHAELADVLTEAVVDSILAIK
  KQDEPIDLFMIEIMEMKHKSETDTSLIRGLVLDHGARHPDMKKRVEDAYILTCNVSLEYE
  KTEVNSGFFYKSAEEREKLVKAERKFIEDRVKKIIELKRKVCGDSDKGFVVINQKGIDPF
  SLDALSKEGIVALRRAKRRNMERLTLACGGVALNSFDDLSPDCLGHAGLVYEYTLGEEKF
  TFIEKCNNPRSVTLLIKGPNKHTLTQIKDAVRDGLRAVKNAIDDGCVVPGAGAVEVAMAE
  ALIKHKPSVKGRAQLGVQAFADALLIIPKVLAQNSGFDLQETLVKIQAEHSESGQLVGVD
  LNTGEPMVAAEVGVWDNYCVKKQLLHSCTVIATNILLVDEIMRAGMSSLKG
• 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. 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)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  RHOBTB2 GTPase cycle (R-HSA-9013418)
  Prefoldin mediated transfer of substrate to CCT/TriC (R-HSA-389957)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[2]
Tourette syndrome	DISX9D54	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[8]
Lung cancer	DISCM4YA	Limited	Biomarker	[1]
Lung carcinoma	DISTR26C	Limited	Biomarker	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]

15 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 T-complex protein 1 subunit zeta (CCT6A).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of T-complex protein 1 subunit zeta (CCT6A).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of T-complex protein 1 subunit zeta (CCT6A).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of T-complex protein 1 subunit zeta (CCT6A).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[17]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of T-complex protein 1 subunit zeta (CCT6A).	[23]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[24]
	DM9CEI5		decreases the expression of T-complex protein 1 subunit zeta (CCT6A).	[25]

2 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 increases the methylation of T-complex protein 1 subunit zeta (CCT6A).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of T-complex protein 1 subunit zeta (CCT6A).	[21]

References

• [1] Bioinformatics analysis of the prognostic value of CCT6A and associated signalling pathways in breast cancer.Mol Med Rep. 2019 May;19(5):4344-4352. doi: 10.3892/mmr.2019.10100. Epub 2019 Mar 28.
• [2] Chaperonin-containing T-complex Protein 1 Subunit Serves as an Autoantigen Recognized by Human V2 T Cells in Autoimmune Diseases.J Biol Chem. 2016 Sep 16;291(38):19985-93. doi: 10.1074/jbc.M115.700070. Epub 2016 Aug 3.
• [3] Overexpressing CCT6A Contributes To Cancer Cell Growth By Affecting The G1-To-S Phase Transition And Predicts A Negative Prognosis In Hepatocellular Carcinoma.Onco Targets Ther. 2019 Nov 29;12:10427-10439. doi: 10.2147/OTT.S229231. eCollection 2019.
• [4] Common variants of HTR3 genes are associated with obsessive-compulsive disorder and its phenotypic expression.Sci Rep. 2016 Sep 12;6:32564. doi: 10.1038/srep32564.
• [5] Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics. 2010 Apr;20(4):274-6. doi: 10.1097/FPC.0b013e328337ce3e.
• [6] Identification of candidate radioresistant genes in human squamous cell carcinoma cells through gene expression analysis using DNA microarrays.Oncol Rep. 2005 Nov;14(5):1293-8.
• [7] There is no evidence for an association between the serotonin receptor 3A gene C178T polymorphism and tardive dyskinesia in Korean schizophrenia patients.Nord J Psychiatry. 2013 Jun;67(3):214-8. doi: 10.3109/08039488.2012.732114. Epub 2012 Nov 6.
• [8] Inhibition of cytosolic chaperonin CCT-1 expression depletes proliferation of colorectal carcinoma in vitro.J Surg Oncol. 2010 Oct 1;102(5):419-23. doi: 10.1002/jso.21625.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] 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.
• [25] A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011 Jan 15;71(2):473-83. doi: 10.1158/0008-5472.CAN-10-1303. Epub 2011 Jan 11.