Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJRY1Y5)

• DOT Name: Sestrin-3 (SESN3)
• Synonyms: EC 1.11.1.-
• Gene Name: SESN3
• Related Disease:
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
  Alzheimer disease
  Atrial fibrillation
  Fatty liver disease
  Intervertebral disc degeneration
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Parkinson disease
  Prostate cancer
  Prostate neoplasm
  Castration-resistant prostate carcinoma
  Lewy body dementia
  Non-insulin dependent diabetes
• UniProt ID: SESN3_HUMAN
• EC Number: 1.11.1.-
• Pfam ID: PF04636
• Sequence:
  MNRGGGSPSAAANYLLCTNCRKVLRKDKRIRVSQPLTRGPSAFIPEKEVVQANTVDERTN
  FLVEEYSTSGRLDNITQVMSLHTQYLESFLRSQFYMLRMDGPLPLPYRHYIAIMAAARHQ
  CSYLINMHVDEFLKTGGIAEWLNGLEYVPQRLKNLNEINKLLAHRPWLITKEHIQKLVKT
  GENNWSLPELVHAVVLLAHYHALASFVFGSGINPERDPEISNGFRLISVNNFCVCDLAND
  NNIENASLSGSNFGIVDSLSELEALMERMKRLQEEREDEEASQEEMSTRFEKEKKESLFV
  VSGDTFHSFPHSDFEDDMIITSDVSRYIEDPGFGYEDFARRGEEHLPTFRAQDYTWENHG
  FSLVNRLYSDIGHLLDEKFRMVYNLTYNTMATHEDVDTTMLRRALFNYVHCMFGIRYDDY
  DYGEVNQLLERSLKVYIKTVTCYPERTTKRMYDSYWRQFKHSEKVHVNLLLMEARMQAEL
  LYALRAITRHLT
• Function: May function as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway. May also regulate the insulin-receptor signaling pathway through activation of TORC2. This metabolic regulator may also play a role in protection against oxidative and genotoxic stresses. May prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  Longevity regulating pathway (hsa04211)
• Reactome Pathway: TP53 Regulates Metabolic Genes (R-HSA-5628897)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[9]
Lewy body dementia	DISAE66J	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[11]

30 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 Sestrin-3 (SESN3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sestrin-3 (SESN3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sestrin-3 (SESN3).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sestrin-3 (SESN3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sestrin-3 (SESN3).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sestrin-3 (SESN3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sestrin-3 (SESN3).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sestrin-3 (SESN3).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sestrin-3 (SESN3).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Sestrin-3 (SESN3).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sestrin-3 (SESN3).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sestrin-3 (SESN3).	[23]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Sestrin-3 (SESN3).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Sestrin-3 (SESN3).	[25]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Sestrin-3 (SESN3).	[26]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Sestrin-3 (SESN3).	[27]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Sestrin-3 (SESN3).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sestrin-3 (SESN3).	[29]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Sestrin-3 (SESN3).	[30]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Sestrin-3 (SESN3).	[12]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Sestrin-3 (SESN3).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sestrin-3 (SESN3).	[32]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Sestrin-3 (SESN3).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sestrin-3 (SESN3).	[34]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Sestrin-3 (SESN3).	[35]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Sestrin-3 (SESN3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sestrin-3 (SESN3).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sestrin-3 (SESN3).	[12]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Sestrin-3 (SESN3).	[37]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide increases the expression of Sestrin-3 (SESN3).	[26]

References

• [1] Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway.Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2685-2693. doi: 10.1016/j.bbadis.2019.07.011. Epub 2019 Jul 24.
• [2] Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers.Clin Cancer Res. 2007 May 15;13(10):2882-9. doi: 10.1158/1078-0432.CCR-06-2367.
• [3] Shared Molecular Signatures Across Neurodegenerative Diseases and Herpes Virus Infections Highlights Potential Mechanisms for Maladaptive Innate Immune Responses.Sci Rep. 2019 Jun 19;9(1):8795. doi: 10.1038/s41598-019-45129-8.
• [4] Upregulation of sestrins protect atriums against oxidative damage and fibrosis in human and experimental atrial fibrillation.Sci Rep. 2017 Apr 11;7:46307. doi: 10.1038/srep46307.
• [5] The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury.Am J Physiol Gastrointest Liver Physiol. 2014 Jul 1;307(1):G58-65. doi: 10.1152/ajpgi.00373.2013. Epub 2014 May 15.
• [6] Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration.J Orthop Res. 2017 Dec;35(12):2682-2691. doi: 10.1002/jor.23583. Epub 2017 May 4.
• [7] Sestrin-3 modulation is essential for therapeutic efficacy of cucurbitacin B in lung cancer cells.Carcinogenesis. 2017 Feb 1;38(2):184-195. doi: 10.1093/carcin/bgw124.
• [8] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [9] Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer.Oncotarget. 2017 Sep 21;8(50):87675-87683. doi: 10.18632/oncotarget.21147. eCollection 2017 Oct 20.
• [10] Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging.Neurosci Lett. 2018 Sep 25;684:35-41. doi: 10.1016/j.neulet.2018.06.052. Epub 2018 Jun 30.
• [11] Sestrin 3 regulation in type 2 diabetic patients and its influence on metabolism and differentiation in skeletal muscle.Am J Physiol Endocrinol Metab. 2013 Dec 1;305(11):E1408-14. doi: 10.1152/ajpendo.00212.2013. Epub 2013 Oct 15.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [16] 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.
• [17] 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.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] 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.
• [20] 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.
• [21] Gypenosides protect retinal pigment epithelium cells from oxidative stress. Food Chem Toxicol. 2018 Feb;112:76-85.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [24] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [25] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [26] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [27] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [28] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [31] OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55. doi: 10.1002/ijc.30256. Epub 2016 Jul 30.
• [32] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [33] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.