Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR4GWJ0)

• DOT Name: Activator of apoptosis harakiri (HRK)
• Synonyms: BH3-interacting domain-containing protein 3; Neuronal death protein DP5
• Gene Name: HRK
• Related Disease:
  Advanced cancer
  Astrocytoma
  Central nervous system lymphoma
  Glioblastoma multiforme
  Leukemia
  Lymphoma
  Neoplasm
  Prostate carcinoma
  Prostate neoplasm
  Type-1/2 diabetes
  Colorectal carcinoma
  Gastric cancer
  Gastric neoplasm
  Prostate cancer
• UniProt ID: HRK_HUMAN
• PDB ID: 2L58; 2L5B; 6XY4; 7P0U
• Pfam ID: PF15196
• Sequence:
  MCPCPLHRGRGPPAVCACSAGRLGLRSSAAQLTAARLKALGDELHQRTMWRRRARSRRAP
  APGALPTYWPWLCAAAQVAALAAWLLGRRNL
• Function: Promotes apoptosis.
• KEGG Pathway: Apoptosis (hsa04210)

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	Genetic Variation	[1]
Astrocytoma	DISL3V18	Strong	Posttranslational Modification	[2]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Altered Expression	[4]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Posttranslational Modification	[6]
Prostate neoplasm	DISHDKGQ	Strong	Posttranslational Modification	[6]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Posttranslational Modification	[8]
Gastric cancer	DISXGOUK	Limited	Posttranslational Modification	[8]
Gastric neoplasm	DISOKN4Y	Limited	Posttranslational Modification	[8]
Prostate cancer	DISF190Y	Limited	Posttranslational Modification	[6]

21 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 Activator of apoptosis harakiri (HRK).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Activator of apoptosis harakiri (HRK).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Activator of apoptosis harakiri (HRK).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Activator of apoptosis harakiri (HRK).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Activator of apoptosis harakiri (HRK).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Activator of apoptosis harakiri (HRK).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Activator of apoptosis harakiri (HRK).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Activator of apoptosis harakiri (HRK).	[16]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Activator of apoptosis harakiri (HRK).	[17]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Activator of apoptosis harakiri (HRK).	[18]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Activator of apoptosis harakiri (HRK).	[19]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Activator of apoptosis harakiri (HRK).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Activator of apoptosis harakiri (HRK).	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Activator of apoptosis harakiri (HRK).	[20]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Activator of apoptosis harakiri (HRK).	[21]
Duvelisib	DM7USVA	Phase 2 Trial	Duvelisib increases the expression of Activator of apoptosis harakiri (HRK).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Activator of apoptosis harakiri (HRK).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Activator of apoptosis harakiri (HRK).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Activator of apoptosis harakiri (HRK).	[9]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Activator of apoptosis harakiri (HRK).	[27]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Activator of apoptosis harakiri (HRK).	[28]

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 Activator of apoptosis harakiri (HRK).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Activator of apoptosis harakiri (HRK).	[26]

References

• [1] The role of HRK gene in human cancer.Oncogene. 2008 Dec;27 Suppl 1:S105-13. doi: 10.1038/onc.2009.48.
• [2] Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas.Acta Neuropathol. 2005 Oct;110(4):402-10. doi: 10.1007/s00401-005-1065-x. Epub 2005 Sep 10.
• [3] Defective expression of HRK is associated with promoter methylation in primary central nervous system lymphomas.Oncology. 2006;70(3):212-21. doi: 10.1159/000094322. Epub 2006 Jun 29.
• [4] Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells.Haematologica. 2002 Sep;87(9):903-7.
• [5] Synergistic silencing by promoter methylation and reduced AP-2 transactivation of the proapoptotic HRK gene confers apoptosis resistance and enhanced tumor growth.Am J Pathol. 2013 Jan;182(1):84-95. doi: 10.1016/j.ajpath.2012.09.018. Epub 2012 Nov 13.
• [6] HRK inactivation associated with promoter methylation and LOH in prostate cancer.Prostate. 2008 Jan 1;68(1):105-13. doi: 10.1002/pros.20600.
• [7] Patient Selection After Mandatory Bundled Payments for Hip and Knee Replacement: Limited Evidence of Lemon-Dropping or Cherry-Picking.J Bone Joint Surg Am. 2020 Feb 19;102(4):325-331. doi: 10.2106/JBJS.19.00756.
• [8] Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer.Clin Cancer Res. 2003 Dec 15;9(17):6410-8.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [15] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [18] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [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] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [22] Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199). Leukemia. 2017 Sep;31(9):1872-1881. doi: 10.1038/leu.2016.382. Epub 2016 Dec 26.
• [23] 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.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] 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.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [28] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.