Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3W6F1U)

• DOT Name: Cysteine and histidine-rich domain-containing protein 1 (CHORDC1)
• Synonyms: CHORD domain-containing protein 1; CHORD-containing protein 1; CHP-1; Protein morgana
• Gene Name: CHORDC1
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Parasitic infection
  Refractory chronic myeloid leukaemia
  Lewy body dementia
  Neoplasm
  Parkinson disease
• UniProt ID: CHRD1_HUMAN
• PDB ID: 2YRT
• Pfam ID: PF04968 ; PF04969
• Sequence:
  MALLCYNRGCGQRFDPETNSDDACTYHPGVPVFHDALKGWSCCKRRTTDFSDFLSIVGCT
  KGRHNSEKPPEPVKPEVKTTEKKELCELKPKFQEHIIQAPKPVEAIKRPSPDEPMTNLEL
  KISASLKQALDKLKLSSGNEENKKEEDNDEIKIGTSCKNGGCSKTYQGLESLEEVCVYHS
  GVPIFHEGMKYWSCCRRKTSDFNTFLAQEGCTKGKHMWTKKDAGKKVVPCRHDWHQTGGE
  VTISVYAKNSLPELSRVEANSTLLNVHIVFEGEKEFDQNVKLWGVIDVKRSYVTMTATKI
  EITMRKAEPMQWASLELPAAKKQEKQKDATTD
• Function: Regulates centrosome duplication, probably by inhibiting the kinase activity of ROCK2. Proposed to act as co-chaperone for HSP90. May play a role in the regulation of NOD1 via a HSP90 chaperone complex. In vitro, has intrinsic chaperone activity. This function may be achieved by inhibiting association of ROCK2 with NPM1. Plays a role in ensuring the localization of the tyrosine kinase receptor EGFR to the plasma membrane, and thus ensures the subsequent regulation of EGFR activity and EGF-induced actin cytoskeleton remodeling. Involved in stress response. Prevents tumorigenesis.
• Tissue Specificity: Underexpressed in many breast and lung cancers.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[3]
Parasitic infection	DISX9CEW	Strong	Biomarker	[4]
Refractory chronic myeloid leukaemia	DIS40YPP	Strong	Biomarker	[3]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[5]

4 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 Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[24]

24 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 Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[17]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[18]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[23]
Celastrol	DMWQIJX	Preclinical	Celastrol increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[29]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Cysteine and histidine-rich domain-containing protein 1 (CHORDC1).	[30]

References

• [1] C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.Leukemia. 2018 Mar;32(3):828-836. doi: 10.1038/leu.2017.280. Epub 2017 Sep 5.
• [2] The IKK/NF-B signalingpathway requires Morgana to drive breast cancer metastasis.Nat Commun. 2017 Nov 21;8(1):1636. doi: 10.1038/s41467-017-01829-1.
• [3] Morgana acts as an oncosuppressor in chronic myeloid leukemia.Blood. 2015 Apr 2;125(14):2245-53. doi: 10.1182/blood-2014-05-575001. Epub 2015 Feb 12.
• [4] Self-selection of plant bioactive compounds by sheep in response to challenge infection with Haemonchus contortus.Physiol Behav. 2018 Oct 1;194:302-310. doi: 10.1016/j.physbeh.2018.06.013. Epub 2018 Jun 12.
• [5] HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson's Disease and Dementia with Lewy Bodies.J Parkinsons Dis. 2019;9(1):97-107. doi: 10.3233/JPD-181443.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] 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.
• [15] 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.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [26] 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.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [30] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.