Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSEA8RS)

• DOT Name: Homeodomain-interacting protein kinase 1 (HIPK1)
• Synonyms: EC 2.7.11.1; Nuclear body-associated kinase 2
• Gene Name: HIPK1
• Related Disease:
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Cervicitis
  Colorectal carcinoma
  Gastrointestinal stromal tumour
  Hypothyroidism
  Prostate cancer
  Prostate carcinoma
  Neoplasm
  Ankylosing spondylitis
  Crohn disease
  Gastric cancer
  Metastatic malignant neoplasm
  Psoriasis
  Sclerosing cholangitis
  Stomach cancer
  Ulcerative colitis
• UniProt ID: HIPK1_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MASQLQVFSPPSVSSSAFCSAKKLKIEPSGWDVSGQSSNDKYYTHSKTLPATQGQANSSH
  QVANFNIPAYDQGLLLPAPAVEHIVVTAADSSGSAATSTFQSSQTLTHRSNVSLLEPYQK
  CGLKRKSEEVDSNGSVQIIEEHPPLMLQNRTVVGAAATTTTVTTKSSSSSGEGDYQLVQH
  EILCSMTNSYEVLEFLGRGTFGQVAKCWKRSTKEIVAIKILKNHPSYARQGQIEVSILSR
  LSSENADEYNFVRSYECFQHKNHTCLVFEMLEQNLYDFLKQNKFSPLPLKYIRPILQQVA
  TALMKLKSLGLIHADLKPENIMLVDPVRQPYRVKVIDFGSASHVSKAVCSTYLQSRYYRA
  PEIILGLPFCEAIDMWSLGCVIAELFLGWPLYPGASEYDQIRYISQTQGLPAEYLLSAGT
  KTTRFFNRDPNLGYPLWRLKTPEEHELETGIKSKEARKYIFNCLDDMAQVNMSTDLEGTD
  MLAEKADRREYIDLLKKMLTIDADKRITPLKTLNHQFVTMTHLLDFPHSNHVKSCFQNME
  ICKRRVHMYDTVSQIKSPFTTHVAPNTSTNLTMSFSNQLNTVHNQASVLASSSTAAAATL
  SLANSDVSLLNYQSALYPSSAAPVPGVAQQGVSLQPGTTQICTQTDPFQQTFIVCPPAFQ
  TGLQATTKHSGFPVRMDNAVPIVPQAPAAQPLQIQSGVLTQGSCTPLMVATLHPQVATIT
  PQYAVPFTLSCAAGRPALVEQTAAVLQAWPGGTQQILLPSTWQQLPGVALHNSVQPTAMI
  PEAMGSGQQLADWRNAHSHGNQYSTIMQQPSLLTNHVTLATAQPLNVGVAHVVRQQQSSS
  LPSKKNKQSAPVSSKSSLDVLPSQVYSLVGSSPLRTTSSYNSLVPVQDQHQPIIIPDTPS
  PPVSVITIRSDTDEEEDNKYKPSSSGLKPRSNVISYVTVNDSPDSDSSLSSPYSTDTLSA
  LRGNSGSVLEGPGRVVADGTGTRTIIVPPLKTQLGDCTVATQASGLLSNKTKPVASVSGQ
  SSGCCITPTGYRAQRGGTSAAQPLNLSQNQQSSAAPTSQERSSNPAPRRQQAFVAPLSQA
  PYTFQHGSPLHSTGHPHLAPAPAHLPSQAHLYTYAAPTSAAALGSTSSIAHLFSPQGSSR
  HAAAYTTHPSTLVHQVPVSVGPSLLTSASVAPAQYQHQFATQSYIGSSRGSTIYTGYPLS
  PTKISQYSYL
• Function: Serine/threonine-protein kinase involved in transcription regulation and TNF-mediated cellular apoptosis. Plays a role as a corepressor for homeodomain transcription factors. Phosphorylates DAXX and MYB. Phosphorylates DAXX in response to stress, and mediates its translocation from the nucleus to the cytoplasm. Inactivates MYB transcription factor activity by phosphorylation. Prevents MAP3K5-JNK activation in the absence of TNF. TNF triggers its translocation to the cytoplasm in response to stress stimuli, thus activating nuclear MAP3K5-JNK by derepression and promoting apoptosis. May be involved in anti-oxidative stress responses. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. Promotes angiogenesis and to be involved in erythroid differentiation. May be involved in malignant squamous cell tumor formation. Phosphorylates PAGE4 at 'Thr-51' which is critical for the ability of PAGE4 to potentiate the transcriptional activator activity of JUN.
• Tissue Specificity: Ubiquitously expressed with highest levels in skeletal muscle and heart. Overexpressed in breast cancer cell lines. Isoform 2 is highly expressed in testis. Expressed in both androgen-dependent and androgen-independent prostate cancer cells .
• KEGG Pathway: Cellular senescence (hsa04218)
• Reactome Pathway:
  Physiological factors (R-HSA-5578768)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[1]
Cervicitis	DIS4KMW5	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[3]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[7]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[6]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[7]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[7]
Stomach cancer	DISKIJSX	Limited	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[7]

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 Homeodomain-interacting protein kinase 1 (HIPK1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homeodomain-interacting protein kinase 1 (HIPK1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Homeodomain-interacting protein kinase 1 (HIPK1).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Homeodomain-interacting protein kinase 1 (HIPK1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Homeodomain-interacting protein kinase 1 (HIPK1).	[24]

14 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 Homeodomain-interacting protein kinase 1 (HIPK1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[18]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[19]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Homeodomain-interacting protein kinase 1 (HIPK1).	[25]

References

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• [2] HIPK1 drives p53 activation to limit colorectal cancer cell growth.Cell Cycle. 2013 Jun 15;12(12):1879-91. doi: 10.4161/cc.24927. Epub 2013 May 15.
• [3] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [5] Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level.Biomolecules. 2019 Feb 22;9(2):77. doi: 10.3390/biom9020077.
• [6] miR-200c/141 Regulates Breast Cancer Stem Cell Heterogeneity via Targeting HIPK1/-Catenin Axis.Theranostics. 2018 Nov 10;8(21):5801-5813. doi: 10.7150/thno.29380. eCollection 2018.
• [7] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [8] In vitro and in vivo effects of miRNA-19b/20a/92a on gastric cancer stem cells and the related mechanism.Int J Med Sci. 2018 Jan 1;15(1):86-94. doi: 10.7150/ijms.21164. eCollection 2018.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
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• [16] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.