Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDB7QC3)

• DOT Name: Homeodomain-interacting protein kinase 2 (HIPK2)
• Synonyms: hHIPk2; EC 2.7.11.1
• Gene Name: HIPK2
• UniProt ID: HIPK2_HUMAN
• PDB ID: 6P5S; 7NCF
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MAPVYEGMASHVQVFSPHTLQSSAFCSVKKLKIEPSSNWDMTGYGSHSKVYSQSKNIPLS
  QPATTTVSTSLPVPNPSLPYEQTIVFPGSTGHIVVTSASSTSVTGQVLGGPHNLMRRSTV
  SLLDTYQKCGLKRKSEEIENTSSVQIIEEHPPMIQNNASGATVATATTSTATSKNSGSNS
  EGDYQLVQHEVLCSMTNTYEVLEFLGRGTFGQVVKCWKRGTNEIVAIKILKNHPSYARQG
  QIEVSILARLSTESADDYNFVRAYECFQHKNHTCLVFEMLEQNLYDFLKQNKFSPLPLKY
  IRPVLQQVATALMKLKSLGLIHADLKPENIMLVDPSRQPYRVKVIDFGSASHVSKAVCST
  YLQSRYYRAPEIILGLPFCEAIDMWSLGCVIAELFLGWPLYPGASEYDQIRYISQTQGLP
  AEYLLSAGTKTTRFFNRDTDSPYPLWRLKTPDDHEAETGIKSKEARKYIFNCLDDMAQVN
  MTTDLEGSDMLVEKADRREFIDLLKKMLTIDADKRITPIETLNHPFVTMTHLLDFPHSTH
  VKSCFQNMEICKRRVNMYDTVNQSKTPFITHVAPSTSTNLTMTFNNQLTTVHNQAPSSTS
  ATISLANPEVSILNYPSTLYQPSAASMAAVAQRSMPLQTGTAQICARPDPFQQALIVCPP
  GFQGLQASPSKHAGYSVRMENAVPIVTQAPGAQPLQIQPGLLAQQAWPSGTQQILLPPAW
  QQLTGVATHTSVQHATVIPETMAGTQQLADWRNTHAHGSHYNPIMQQPALLTGHVTLPAA
  QPLNVGVAHVMRQQPTSTTSSRKSKQHQSSVRNVSTCEVSSSQAISSPQRSKRVKENTPP
  RCAMVHSSPACSTSVTCGWGDVASSTTRERQRQTIVIPDTPSPTVSVITISSDTDEEEEQ
  KHAPTSTVSKQRKNVISCVTVHDSPYSDSSSNTSPYSVQQRAGHNNANAFDTKGSLENHC
  TGNPRTIIVPPLKTQASEVLVECDSLVPVNTSHHSSSYKSKSSSNVTSTSGHSSGSSSGA
  ITYRQQRPGPHFQQQQPLNLSQAQQHITTDRTGSHRRQQAYITPTMAQAPYSFPHNSPSH
  GTVHPHLAAAAAAAHLPTQPHLYTYTAPAALGSTGTVAHLVASQGSARHTVQHTAYPASI
  VHQVPVSMGPRVLPSPTIHPSQYPAQFAHQTYISASPASTVYTGYPLSPAKVNQYPYI
• Function: Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1, ZBTB4 and DAZAP2. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. In response to DNA damage, phosphorylates DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal degradation. Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.
• Tissue Specificity: Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors.
• KEGG Pathway: Cellular senescence (hsa04218)
• Reactome Pathway:
  SUMOylation of transcription cofactors (R-HSA-3899300)
  Physiological factors (R-HSA-5578768)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

3 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 2 (HIPK2).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Homeodomain-interacting protein kinase 2 (HIPK2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeodomain-interacting protein kinase 2 (HIPK2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the activity of Homeodomain-interacting protein kinase 2 (HIPK2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[17]
Etoposide	DMNH3PG	Approved	Etoposide increases the activity of Homeodomain-interacting protein kinase 2 (HIPK2).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[13]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[22]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[26]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[27]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Homeodomain-interacting protein kinase 2 (HIPK2).	[28]

References

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