Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJN51OC)

• DOT Name: Zinc finger protein Pegasus (IKZF5)
• Synonyms: Ikaros family zinc finger protein 5
• Gene Name: IKZF5
• Related Disease:
  Acute lymphocytic leukaemia
  Acute myocardial infarction
  Childhood acute lymphoblastic leukemia
  High blood pressure
  Myocardial infarction
  Prostate cancer
  Prostate carcinoma
  Stroke
  Thrombocytopenia
  Thrombocytopenia 7
  Obsolete autosomal thrombocytopenia with normal platelets
  Type-1/2 diabetes
• UniProt ID: IKZF5_HUMAN
• Sequence:
  MGEKKPEPLDFVKDFQEYLTQQTHHVNMISGSVSGDKEAEALQGAGTDGDQNGLDHPSVE
  VSLDENSGMLVDGFERTFDGKLKCRYCNYASKGTARLIEHIRIHTGEKPHRCHLCPFASA
  YERHLEAHMRSHTGEKPYKCELCSFRCSDRSNLSHHRRRKHKMVPIKGTRSSLSSKKMWG
  VLQKKTSNLGYSRRALINLSPPSMVVQKPDYLNDFTHEIPNIQTDSYESMAKTTPTGGLP
  RDPQELMVDNPLNQLSTLAGQLSSLPPENQNPASPDVVPCPDEKPFMIQQPSTQAVVSAV
  SASIPQSSSPTSPEPRPSHSQRNYSPVAGPSSEPSAHTSTPSIGNSQPSTPAPALPVQDP
  QLLHHCQHCDMYFADNILYTIHMGCHGYENPFQCNICGCKCKNKYDFACHFARGQHNQH
• Function: Transcriptional repressor that binds the core 5'GNNTGTNG-3' DNA consensus sequence. Involved in megakaryocyte differentiation.
• Tissue Specificity: Expressed in brain, heart, skeletal muscle, kidney, and liver. Expressed in the hematopoietic cell lines MOLT-4, NALM-6 and K-562. Highly expressed in THP-1 and M-07e cell lines, which have characteristics of myeloid and early megakaryocytic cells respectively.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[5]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Thrombocytopenia	DISU61YW	Strong	Altered Expression	[7]
Thrombocytopenia 7	DISDFM4V	Strong	Autosomal dominant	[8]
Obsolete autosomal thrombocytopenia with normal platelets	DISHFIE8	Supportive	Autosomal dominant	[7]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Zinc finger protein Pegasus (IKZF5).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Zinc finger protein Pegasus (IKZF5).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc finger protein Pegasus (IKZF5).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc finger protein Pegasus (IKZF5).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Zinc finger protein Pegasus (IKZF5).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger protein Pegasus (IKZF5).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Zinc finger protein Pegasus (IKZF5).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Zinc finger protein Pegasus (IKZF5).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Zinc finger protein Pegasus (IKZF5).	[20]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Zinc finger protein Pegasus (IKZF5).	[21]

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 affects the methylation of Zinc finger protein Pegasus (IKZF5).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Zinc finger protein Pegasus (IKZF5).	[19]

References

• [1] Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations.Cancer Epidemiol Biomarkers Prev. 2017 Oct;26(10):1531-1539. doi: 10.1158/1055-9965.EPI-17-0360. Epub 2017 Jul 27.
• [2] A new score based on the PEGASUS-TIMI 54 criteria for risk stratification of patients with acute myocardial infarction.Int J Cardiol. 2019 Mar 1;278:1-6. doi: 10.1016/j.ijcard.2018.11.142. Epub 2018 Dec 4.
• [3] Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.PLoS Genet. 2010 Oct 28;6(10):e1001177. doi: 10.1371/journal.pgen.1001177.
• [4] Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54.Eur Heart J Cardiovasc Pharmacother. 2019 Oct 1;5(4):200-206. doi: 10.1093/ehjcvp/pvz020.
• [5] TET2 binds the androgen receptor and loss is associated with prostate cancer.Oncogene. 2017 Apr;36(15):2172-2183. doi: 10.1038/onc.2016.376. Epub 2016 Nov 7.
• [6] Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients WithMultivessel Coronary Disease.J Am Coll Cardiol. 2018 Feb 6;71(5):489-496. doi: 10.1016/j.jacc.2017.11.050.
• [7] Germline mutations in the transcription factor IKZF5 cause thrombocytopenia. Blood. 2019 Dec 5;134(23):2070-2081. doi: 10.1182/blood.2019000782.
• [8] Prevalence of primary immune thrombocytopenia in Oklahoma. Am J Hematol. 2012 Sep;87(9):848-52. doi: 10.1002/ajh.23262. Epub 2012 Jun 5.
• [9] Consistent platelet inhibition with ticagrelor 60 mg twice-daily following myocardial infarction regardless of diabetes status.Thromb Haemost. 2017 May 3;117(5):940-947. doi: 10.1160/TH16-09-0703. Epub 2017 Mar 16.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.