Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BV82K)

• DOT Name: Notchless protein homolog 1 (NLE1)
• Gene Name: NLE1
• Related Disease:
  Vitiligo
  Absence epilepsy
  Hemolytic-uremic syndrome
• UniProt ID: NLE1_HUMAN
• PDB ID: 6WAJ; 8FL0; 8FL2; 8FL3; 8FL4; 8INK; 8IPD; 8IPX; 8IPY; 8IR1; 8IR3
• Pfam ID: PF08154 ; PF00400
• Sequence:
  MAAAVPDEAVARDVQRLLVQFQDEGGQLLGSPFDVPVDITPDRLQLVCNALLAQEDPLPL
  AFFVHDAEIVSSLGKTLESQAVETEKVLDIIYQPQAIFRVRAVTRCTSSLEGHSEAVISV
  AFSPTGKYLASGSGDTTVRFWDLSTETPHFTCKGHRHWVLSISWSPDGRKLASGCKNGQI
  LLWDPSTGKQVGRTLAGHSKWITGLSWEPLHANPECRYVASSSKDGSVRIWDTTAGRCER
  ILTGHTQSVTCLRWGGDGLLYSASQDRTIKVWRAHDGVLCRTLQGHGHWVNTMALSTDYA
  LRTGAFEPAEASVNPQDLQGSLQELKERALSRYNLVRGQGPERLVSGSDDFTLFLWSPAE
  DKKPLTRMTGHQALINQVLFSPDSRIVASASFDKSIKLWDGRTGKYLASLRGHVAAVYQI
  AWSADSRLLVSGSSDSTLKVWDVKAQKLAMDLPGHADEVYAVDWSPDGQRVASGGKDKCL
  RIWRR
• Function: Plays a role in regulating Notch activity. Plays a role in regulating the expression of CDKN1A and several members of the Wnt pathway, probably via its effects on Notch activity. Required during embryogenesis for inner mass cell survival.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vitiligo	DISR05SL	Strong	Genetic Variation	[1]
Absence epilepsy	DISJPOUD	Limited	Altered Expression	[2]
Hemolytic-uremic syndrome	DISSCBGW	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Notchless protein homolog 1 (NLE1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Notchless protein homolog 1 (NLE1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Notchless protein homolog 1 (NLE1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Notchless protein homolog 1 (NLE1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Notchless protein homolog 1 (NLE1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Notchless protein homolog 1 (NLE1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Notchless protein homolog 1 (NLE1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Notchless protein homolog 1 (NLE1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Notchless protein homolog 1 (NLE1).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Notchless protein homolog 1 (NLE1).	[13]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Notchless protein homolog 1 (NLE1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Notchless protein homolog 1 (NLE1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Notchless protein homolog 1 (NLE1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Notchless protein homolog 1 (NLE1).	[17]

References

• [1] An In-Vitro Assay Estimating Changes in Melanin Content of Melanoma Cells due to Ultra-Dilute, Potentized Preparations.Homeopathy. 2019 Aug;108(3):183-187. doi: 10.1055/s-0039-1678541. Epub 2019 Mar 5.
• [2] Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy.Brain Struct Funct. 2017 Aug;222(6):2773-2785. doi: 10.1007/s00429-017-1371-9. Epub 2017 Feb 16.
• [3] Molecular analysis as an aid to assess the public health risk of non-O157 Shiga toxin-producing Escherichia coli strains.Appl Environ Microbiol. 2008 Apr;74(7):2153-60. doi: 10.1128/AEM.02566-07. Epub 2008 Feb 1.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.