Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW7JEHV)

• DOT Name: Transcription factor HES-5 (HES5)
• Synonyms: Class B basic helix-loop-helix protein 38; bHLHb38; Hairy and enhancer of split 5
• Gene Name: HES5
• Related Disease:
  Cognitive impairment
  Cone-rod dystrophy 2
  Neuroblastoma
  Arterial disorder
  Astrocytoma
  Bone disease
  Brain cancer
  Brain neoplasm
  Colonic neoplasm
  Diabetic retinopathy
  Endometriosis
  Hepatocellular carcinoma
  Lung neoplasm
  Non-small-cell lung cancer
  Osteoarthritis
  Plasma cell myeloma
  Glioma
  Kennedy disease
  Neoplasm
  Nervous system disease
  Prostate cancer
  Prostate carcinoma
• UniProt ID: HES5_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MAPSTVAVELLSPKEKNRLRKPVVEKMRRDRINSSIEQLKLLLEQEFARHQPNSKLEKAD
  ILEMAVSYLKHSKAFVAAAGPKSLHQDYSEGYSWCLQEAVQFLTLHAASDTQMKLLYHFQ
  RPPAAPAAPAKEPKAPGAAPPPALSAKATAAAAAAHQPACGLWRPW
• Function: Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator.
• Tissue Specificity: Expressed in fetal heart and brain tumors.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
• Reactome Pathway:
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Altered Expression	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Definitive	Posttranslational Modification	[3]
Arterial disorder	DISLG4XS	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Bone disease	DISE1F82	Strong	Altered Expression	[6]
Brain cancer	DISBKFB7	Strong	Biomarker	[7]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[8]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[9]
Endometriosis	DISX1AG8	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[14]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Disputed	Altered Expression	[15]
Kennedy disease	DISXZVM1	Limited	Altered Expression	[16]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[17]
Prostate cancer	DISF190Y	Limited	Altered Expression	[18]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription factor HES-5 (HES5).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor HES-5 (HES5).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor HES-5 (HES5).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor HES-5 (HES5).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor HES-5 (HES5).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor HES-5 (HES5).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transcription factor HES-5 (HES5).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transcription factor HES-5 (HES5).	[23]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Transcription factor HES-5 (HES5).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcription factor HES-5 (HES5).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Transcription factor HES-5 (HES5).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor HES-5 (HES5).	[27]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Transcription factor HES-5 (HES5).	[28]

References

• [1] Risperidone ameliorates cognitive deficits, promotes hippocampal proliferation, and enhances Notch signaling in a murine model of schizophrenia.Pharmacol Biochem Behav. 2017 Dec;163:101-109. doi: 10.1016/j.pbb.2017.09.010. Epub 2017 Oct 14.
• [2] Progesterone effects on oligodendrocyte differentiation in injured spinal cord.Brain Res. 2019 Apr 1;1708:36-46. doi: 10.1016/j.brainres.2018.12.005. Epub 2018 Dec 5.
• [3] Notch pathway activation induces neuroblastoma tumor cell growth arrest.Pediatr Blood Cancer. 2012 May;58(5):682-9. doi: 10.1002/pbc.23202. Epub 2011 Jul 8.
• [4] Green tea polyphenols protect against preglomerular arteriopathy via the jagged1/notch1 pathway.Am J Transl Res. 2018 Oct 15;10(10):3276-3290. eCollection 2018.
• [5] Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.Mol Cell Biochem. 2008 Jan;307(1-2):101-8. doi: 10.1007/s11010-007-9589-0. Epub 2007 Sep 12.
• [6] Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche.Oncotarget. 2016 Aug 30;7(35):56013-56029. doi: 10.18632/oncotarget.10820.
• [7] Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.Genes Cancer. 2010 Aug;1(8):822-35. doi: 10.1177/1947601910383564.
• [8] Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling.Oncogene. 2015 Jul 23;34(30):3935-3945. doi: 10.1038/onc.2014.324. Epub 2014 Sep 29.
• [9] DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders.Sci Rep. 2017 Sep 18;7(1):11762. doi: 10.1038/s41598-017-12084-1.
• [10] Decreased Notch pathway signaling in the endometrium of women with endometriosis impairs decidualization.J Clin Endocrinol Metab. 2015 Mar;100(3):E433-42. doi: 10.1210/jc.2014-3720. Epub 2014 Dec 29.
• [11] HES5 promotes cell proliferation and invasion through activation of STAT3 and predicts poor survival in hepatocellular carcinoma.Exp Mol Pathol. 2015 Dec;99(3):474-84. doi: 10.1016/j.yexmp.2015.09.002. Epub 2015 Sep 3.
• [12] Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung.Cancer Res. 2007 Sep 1;67(17):7954-9. doi: 10.1158/0008-5472.CAN-07-1229.
• [13] HES5 promotes cellular proliferation of non-small cell lung cancer through STAT3 signaling.Oncol Rep. 2017 Jan;37(1):474-482. doi: 10.3892/or.2016.5268. Epub 2016 Nov 22.
• [14] Notch1, Jagged1, and HES5 are abundantly expressed in osteoarthritis.Cells Tissues Organs. 2008;188(3):287-98. doi: 10.1159/000121610. Epub 2008 Mar 20.
• [15] Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.J Neurosci. 2006 Feb 8;26(6):1864-71. doi: 10.1523/JNEUROSCI.2643-05.2006.
• [16] DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5.EMBO Mol Med. 2019 May;11(5):e8547. doi: 10.15252/emmm.201708547.
• [17] A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.Arch Toxicol. 2013 Apr;87(4):721-33. doi: 10.1007/s00204-012-0984-2. Epub 2012 Dec 2.
• [18] HES5 silencing is an early and recurrent change in prostate tumourigenesis.Endocr Relat Cancer. 2015 Apr;22(2):131-44. doi: 10.1530/ERC-14-0454. Epub 2015 Jan 5.
• [19] 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.
• [20] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun. 2014 Mar 31;2:31. doi: 10.1186/2051-5960-2-31.
• [23] 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.
• [24] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [25] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [26] 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.
• [27] 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.
• [28] Glyphosate-based herbicide induces long-lasting impairment in neuronal and glial differentiation. Environ Toxicol. 2022 Aug;37(8):2044-2057. doi: 10.1002/tox.23549. Epub 2022 Apr 29.