Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT889IXY)

• DOT Name: Sestrin-2 (SESN2)
• Synonyms: EC 1.11.1.-; Hypoxia-induced gene
• Gene Name: SESN2
• Related Disease:
  Colorectal neoplasm
  Hemangioblastoma
  Rheumatoid arthritis
  Von hippel-lindau disease
  Adult glioblastoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  B-cell neoplasm
  Breast cancer
  Carcinoma
  Cardiomyopathy
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Epithelial ovarian cancer
  Fetal growth restriction
  Gastric cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  High blood pressure
  Melanoma
  Neuroblastoma
  Non-insulin dependent diabetes
  Obesity
  Obstructive sleep apnea
  Ovarian cancer
  Pancreatic cancer
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Pulmonary arterial hypertension
  Pulmonary emphysema
  Stomach cancer
  Stroke
  Breast carcinoma
  Head-neck squamous cell carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Clear cell renal carcinoma
  Colonic neoplasm
  Glioma
  Metastatic malignant neoplasm
  Renal cell carcinoma
  Type-1/2 diabetes
• UniProt ID: SESN2_HUMAN
• PDB ID: 5CUF; 5DJ4; 5T0N; 6N0M
• EC Number: 1.11.1.-
• Pfam ID: PF04636
• Sequence:
  MIVADSECRAELKDYLRFAPGGVGDSGPGEEQRESRARRGPRGPSAFIPVEEVLREGAES
  LEQHLGLEALMSSGRVDNLAVVMGLHPDYFTSFWRLHYLLLHTDGPLASSWRHYIAIMAA
  ARHQCSYLVGSHMAEFLQTGGDPEWLLGLHRAPEKLRKLSEINKLLAHRPWLITKEHIQA
  LLKTGEHTWSLAELIQALVLLTHCHSLSSFVFGCGILPEGDADGSPAPQAPTPPSEQSSP
  PSRDPLNNSGGFESARDVEALMERMQQLQESLLRDEGTSQEEMESRFELEKSESLLVTPS
  ADILEPSPHPDMLCFVEDPTFGYEDFTRRGAQAPPTFRAQDYTWEDHGYSLIQRLYPEGG
  QLLDEKFQAAYSLTYNTIAMHSGVDTSVLRRAIWNYIHCVFGIRYDDYDYGEVNQLLERN
  LKVYIKTVACYPEKTTRRMYNLFWRHFRHSEKVHVNLLLLEARMQAALLYALRAITRYMT
• Function: Functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents mTORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway. This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1. May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1. May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein. Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  mTOR sig.ling pathway (hsa04150)
  Longevity regulating pathway (hsa04211)
• Reactome Pathway:
  Amino acids regulate mTORC1 (R-HSA-9639288)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Hemangioblastoma	DIS1EAZC	Definitive	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
Von hippel-lindau disease	DIS6ZFQQ	Definitive	Altered Expression	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[7]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[7]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Carcinoma	DISH9F1N	Strong	Altered Expression	[10]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[11]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[13]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[15]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
High blood pressure	DISY2OHH	Strong	Biomarker	[17]
Melanoma	DIS1RRCY	Strong	Altered Expression	[18]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[20]
Obesity	DIS47Y1K	Strong	Altered Expression	[21]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[22]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[13]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[23]
Parkinson disease	DISQVHKL	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[25]
Pulmonary emphysema	DIS5M7HZ	Strong	Biomarker	[26]
Stomach cancer	DISKIJSX	Strong	Biomarker	[15]
Stroke	DISX6UHX	Strong	Biomarker	[27]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[9]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[28]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[29]
Lung cancer	DISCM4YA	moderate	Biomarker	[30]
Lung carcinoma	DISTR26C	moderate	Biomarker	[30]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[12]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[31]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[32]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[1]
Glioma	DIS5RPEH	Limited	Biomarker	[33]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[34]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[32]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sestrin-2 (SESN2).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sestrin-2 (SESN2).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sestrin-2 (SESN2).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sestrin-2 (SESN2).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sestrin-2 (SESN2).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sestrin-2 (SESN2).	[41]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sestrin-2 (SESN2).	[42]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sestrin-2 (SESN2).	[43]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sestrin-2 (SESN2).	[44]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Sestrin-2 (SESN2).	[45]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sestrin-2 (SESN2).	[46]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sestrin-2 (SESN2).	[47]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sestrin-2 (SESN2).	[48]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sestrin-2 (SESN2).	[49]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sestrin-2 (SESN2).	[50]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Sestrin-2 (SESN2).	[51]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Sestrin-2 (SESN2).	[52]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sestrin-2 (SESN2).	[48]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sestrin-2 (SESN2).	[53]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Sestrin-2 (SESN2).	[54]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Sestrin-2 (SESN2).	[55]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Sestrin-2 (SESN2).	[56]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Sestrin-2 (SESN2).	[57]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Sestrin-2 (SESN2).	[44]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Sestrin-2 (SESN2).	[58]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Sestrin-2 (SESN2).	[58]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Sestrin-2 (SESN2).	[44]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of Sestrin-2 (SESN2).	[59]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sestrin-2 (SESN2).	[60]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Sestrin-2 (SESN2).	[42]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sestrin-2 (SESN2).	[61]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sestrin-2 (SESN2).	[62]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Sestrin-2 (SESN2).	[63]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sestrin-2 (SESN2).	[65]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sestrin-2 (SESN2).	[66]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sestrin-2 (SESN2).	[67]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 increases the expression of Sestrin-2 (SESN2).	[68]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Piperazinyl methyl quinazolinone derivative 2 increases the expression of Sestrin-2 (SESN2).	[59]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sestrin-2 (SESN2).	[69]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sestrin-2 (SESN2).	[70]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sestrin-2 (SESN2).	[71]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sestrin-2 (SESN2).	[72]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sestrin-2 (SESN2).	[42]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Sestrin-2 (SESN2).	[73]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sestrin-2 (SESN2).	[44]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Sestrin-2 (SESN2).	[74]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of Sestrin-2 (SESN2).	[1]
Buthionine sulfoximine	DMJ46CB	Investigative	Buthionine sulfoximine increases the expression of Sestrin-2 (SESN2).	[59]
A192621	DMV8AH6	Investigative	A192621 increases the expression of Sestrin-2 (SESN2).	[76]

1 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 Sestrin-2 (SESN2).	[64]

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