Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT7VPRB)

• DOT Name: Histone H1.3 (H1-3)
• Synonyms: Histone H1c; Histone H1s-2
• Gene Name: H1-3
• Related Disease: Stroke
• UniProt ID: H13_HUMAN
• PDB ID: 7XX5
• Pfam ID: PF00538
• Sequence:
  MSETAPLAPTIPAPAEKTPVKKKAKKAGATAGKRKASGPPVSELITKAVAASKERSGVSL
  AALKKALAAAGYDVEKNNSRIKLGLKSLVSKGTLVQTKGTGASGSFKLNKKAASGEGKPK
  AKKAGAAKPRKPAGAAKKPKKVAGAATPKKSIKKTPKKVKKPATAAGTKKVAKSAKKVKT
  PQPKKAAKSPAKAKAPKPKAAKPKSGKPKVTKAKKAAPKKK
• Function: Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation.
• Reactome Pathway:
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)
  Apoptosis induced DNA fragmentation (R-HSA-140342)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stroke	DISX6UHX	Limited	Biomarker	[1]

18 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 Histone H1.3 (H1-3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone H1.3 (H1-3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone H1.3 (H1-3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone H1.3 (H1-3).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Histone H1.3 (H1-3).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Histone H1.3 (H1-3).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Histone H1.3 (H1-3).	[8]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Histone H1.3 (H1-3).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Histone H1.3 (H1-3).	[3]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Histone H1.3 (H1-3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone H1.3 (H1-3).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Histone H1.3 (H1-3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone H1.3 (H1-3).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Histone H1.3 (H1-3).	[14]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Histone H1.3 (H1-3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone H1.3 (H1-3).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone H1.3 (H1-3).	[2]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Histone H1.3 (H1-3).	[17]

References

• [1] Smoking affects gene expression in blood of patients with ischemic stroke.Ann Clin Transl Neurol. 2019 Sep;6(9):1748-1756. doi: 10.1002/acn3.50876. Epub 2019 Aug 22.
• [2] 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.
• [3] 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.
• [4] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [5] 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.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [8] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [9] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [10] 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.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [15] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.