Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLMBUZ6)

• DOT Name: Signal transducer and activator of transcription 1-alpha/beta (STAT1)
• Synonyms: Transcription factor ISGF-3 components p91/p84
• Gene Name: STAT1
• Related Disease:
  Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome
  Immunodeficiency 31B
  Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
• UniProt ID: STAT1_HUMAN
• PDB ID: 1BF5; 1YVL; 2KA6; 3WWT; 7NUF; 8D3F
• Pfam ID: PF00017 ; PF12162 ; PF01017 ; PF02864 ; PF02865 ; PF21354
• Sequence:
  MSQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDL
  LSQLDDQYSRFSLENNFLLQHNIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQ
  RFNQAQSGNIQSTVMLDKQKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNR
  EHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKIIELLNVTELTQNALINDELVEWK
  RRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKNKQV
  LWDRTFSLFQQLIQSSFVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKV
  KVLFDKDVNERNTVKGFRKFNILGTHTKVMNMEESTNGSLAAEFRHLQLKEQKNAGTRTN
  EGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWYNMLVAE
  PRNLSFFLTPPCARWAQLSEVLSWQFSSVTKRGLNVDQLNMLGEKLLGPNASPDGLIPWT
  RFCKENINDKNFPFWLWIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFL
  LRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTKKELSAVTFPDIIRNYKVMAAENIP
  ENPLKYLYPNIDKDHAFGKYYSRPKEAPEPMELDGPKGTGYIKTELISVSEVHPSRLQTT
  DNLLPMSPEEFDEVSRIVGSVEFDSMMNTV
• Function: Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Involved in food tolerance in small intestine: associates with the Gasdermin-D, p13 cleavage product (13 kDa GSDMD) and promotes transcription of CIITA, inducing type 1 regulatory T (Tr1) cells in upper small intestine.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Prolactin sig.ling pathway (hsa04917)
  Thyroid hormone sig.ling pathway (hsa04919)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Pancreatic cancer (hsa05212)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  Signaling by cytosolic FGFR1 fusion mutants (R-HSA-1839117)
  Downstream signal transduction (R-HSA-186763)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Interleukin-20 family signaling (R-HSA-8854691)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Interleukin-35 Signalling (R-HSA-8984722)
  Interleukin-9 signaling (R-HSA-8985947)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  Interleukin-27 signaling (R-HSA-9020956)
  Interleukin-21 signaling (R-HSA-9020958)
  Interferon alpha/beta signaling (R-HSA-909733)
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants (R-HSA-9673767)
  Signaling by PDGFRA extracellular domain mutants (R-HSA-9673770)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Growth hormone receptor signaling (R-HSA-982772)
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	DISR0FN3	Definitive	Autosomal dominant	[1]
Immunodeficiency 31B	DISY5F50	Definitive	Autosomal recessive	[2]
Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	DIS50C2I	Strong	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Signal transducer and activator of transcription 1-alpha/beta (STAT1) increases the response to substance of Cisplatin.	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[15]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[23]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[24]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[25]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[15]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[7]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[26]
Busulfan	DMXYJ9C	Approved	Busulfan affects the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[27]
Interferon alfa-2B	DMWCQP4	Approved	Interferon alfa-2B increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[28]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[29]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[30]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[31]
Jakafi	DMNORK8	Phase 3	Jakafi decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[32]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[33]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[34]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[36]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[39]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[40]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[41]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[42]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[43]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[44]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[44]
Ro 41-5253	DMSJLWP	Investigative	Ro 41-5253 decreases the expression of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[46]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the localization of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Irinotecan increases the phosphorylation of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[21]
Raltitrexed	DMT9K8G	Approved	Raltitrexed increases the phosphorylation of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[37]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[37]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Signal transducer and activator of transcription 1-alpha/beta (STAT1).	[45]

References

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