Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTS3SXE)

• DOT Name: Serine/threonine-protein kinase SMG1 (SMG1)
• Synonyms: SMG-1; hSMG-1; EC 2.7.11.1; Lambda/iota protein kinase C-interacting protein; Lambda-interacting protein; Nonsense mediated mRNA decay-associated PI3K-related kinase SMG1
• Gene Name: SMG1
• Related Disease:
  Acute myelogenous leukaemia
  Anaplastic large cell lymphoma
  Bladder cancer
  Carcinoma
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Human papillomavirus infection
  Hyperthyroidism
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Plasma cell myeloma
  Renal cell carcinoma
  Schizophrenia
  Scleroderma
  Skin disease
  Systemic sclerosis
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Tuberculosis
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Neuroblastoma
  Pancreatic adenocarcinoma
  Squamous cell carcinoma
  Triple negative breast cancer
  Arthritis
  Cerebral infarction
  Nervous system disease
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Lewy body dementia
  Malignant pleural mesothelioma
  Nasopharyngeal carcinoma
  Pancreatic cancer
  Parkinson disease
  Rheumatoid arthritis
  Thyroid gland papillary carcinoma
• UniProt ID: SMG1_HUMAN
• PDB ID: 6L53; 6L54; 6SYT; 6Z3R; 7PW4; 7PW5; 7PW6; 7PW7; 7PW8; 7PW9
• EC Number: 2.7.11.1
• Pfam ID: PF02260 ; PF00454 ; PF15785 ; PF17229
• Sequence:
  MSRRAPGSRLSSGGGGGGTKYPRSWNDWQPRTDSASADPDNLKYSSSRDRGGSSSYGLQP
  SNSAVVSRQRHDDTRVHADIQNDEKGGYSVNGGSGENTYGRKSLGQELRVNNVTSPEFTS
  VQHGSRALATKDMRKSQERSMSYSDESRLSNLLRRITREDDRDRRLATVKQLKEFIQQPE
  NKLVLVKQLDNILAAVHDVLNESSKLLQELRQEGACCLGLLCASLSYEAEKIFKWIFSKF
  SSSAKDEVKLLYLCATYKALETVGEKKAFSSVMQLVMTSLQSILENVDTPELLCKCVKCI
  LLVARCYPHIFSTNFRDTVDILVGWHIDHTQKPSLTQQVSGWLQSLEPFWVADLAFSTTL
  LGQFLEDMEAYAEDLSHVASGESVDEDVPPPSVSLPKLAALLRVFSTVVRSIGERFSPIR
  GPPITEAYVTDVLYRVMRCVTAANQVFFSEAVLTAANECVGVLLGSLDPSMTIHCDMVIT
  YGLDQLENCQTCGTDYIISVLNLLTLIVEQINTKLPSSFVEKLFIPSSKLLFLRYHKEKE
  VVAVAHAVYQAVLSLKNIPVLETAYKLILGEMTCALNNLLHSLQLPEACSEIKHEAFKNH
  VFNVDNAKFVVIFDLSALTTIGNAKNSLIGMWALSPTVFALLSKNLMIVHSDLAVHFPAI
  QYAVLYTLYSHCTRHDHFISSSLSSSSPSLFDGAVISTVTTATKKHFSIILNLLGILLKK
  DNLNQDTRKLLMTWALEAAVLMKKSETYAPLFSLPSFHKFCKGLLANTLVEDVNICLQAC
  SSLHALSSSLPDDLLQRCVDVCRVQLVHSGTRIRQAFGKLLKSIPLDVVLSNNNHTEIQE
  ISLALRSHMSKAPSNTFHPQDFSDVISFILYGNSHRTGKDNWLERLFYSCQRLDKRDQST
  IPRNLLKTDAVLWQWAIWEAAQFTVLSKLRTPLGRAQDTFQTIEGIIRSLAAHTLNPDQD
  VSQWTTADNDEGHGNNQLRLVLLLQYLENLEKLMYNAYEGCANALTSPPKVIRTFFYTNR
  QTCQDWLTRIRLSIMRVGLLAGQPAVTVRHGFDLLTEMKTTSLSQGNELEVTIMMVVEAL
  CELHCPEAIQGIAVWSSSIVGKNLLWINSVAQQAEGRFEKASVEYQEHLCAMTGVDCCIS
  SFDKSVLTLANAGRNSASPKHSLNGESRKTVLSKPTDSSPEVINYLGNKACECYISIADW
  AAVQEWQNAIHDLKKSTSSTSLNLKADFNYIKSLSSFESGKFVECTEQLELLPGENINLL
  AGGSKEKIDMKKLLPNMLSPDPRELQKSIEVQLLRSSVCLATALNPIEQDQKWQSITENV
  VKYLKQTSRIAIGPLRLSTLTVSQSLPVLSTLQLYCSSALENTVSNRLSTEDCLIPLFSE
  ALRSCKQHDVRPWMQALRYTMYQNQLLEKIKEQTVPIRSHLMELGLTAAKFARKRGNVSL
  ATRLLAQCSEVQLGKTTTAQDLVQHFKKLSTQGQVDEKWGPELDIEKTKLLYTAGQSTHA
  MEMLSSCAISFCKSVKAEYAVAKSILTLAKWIQAEWKEISGQLKQVYRAQHQQNFTGLST
  LSKNILTLIELPSVNTMEEEYPRIESESTVHIGVGEPDFILGQLYHLSSVQAPEVAKSWA
  ALASWAYRWGRKVVDNASQGEGVRLLPREKSEVQNLLPDTITEEEKERIYGILGQAVCRP
  AGIQDEDITLQITESEDNEEDDMVDVIWRQLISSCPWLSELDESATEGVIKVWRKVVDRI
  FSLYKLSCSAYFTFLKLNAGQIPLDEDDPRLHLSHRVEQSTDDMIVMATLRLLRLLVKHA
  GELRQYLEHGLETTPTAPWRGIIPQLFSRLNHPEVYVRQSICNLLCRVAQDSPHLILYPA
  IVGTISLSSESQASGNKFSTAIPTLLGNIQGEELLVSECEGGSPPASQDSNKDEPKSGLN
  EDQAMMQDCYSKIVDKLSSANPTMVLQVQMLVAELRRVTVLWDELWLGVLLQQHMYVLRR
  IQQLEDEVKRVQNNNTLRKEEKIAIMREKHTALMKPIVFALEHVRSITAAPAETPHEKWF
  QDNYGDAIENALEKLKTPLNPAKPGSSWIPFKEIMLSLQQRAQKRASYILRLEEISPWLA
  AMTNTEIALPGEVSARDTVTIHSVGGTITILPTKTKPKKLLFLGSDGKSYPYLFKGLEDL
  HLDERIMQFLSIVNTMFATINRQETPRFHARHYSVTPLGTRSGLIQWVDGATPLFGLYKR
  WQQREAALQAQKAQDSYQTPQNPGIVPRPSELYYSKIGPALKTVGLSLDVSRRDWPLHVM
  KAVLEELMEATPPNLLAKELWSSCTTPDEWWRVTQSYARSTAVMSMVGYIIGLGDRHLDN
  VLIDMTTGEVVHIDYNVCFEKGKSLRVPEKVPFRMTQNIETALGVTGVEGVFRLSCEQVL
  HIMRRGRETLLTLLEAFVYDPLVDWTAGGEAGFAGAVYGGGGQQAESKQSKREMEREITR
  SLFSSRVAEIKVNWFKNRDEMLVVLPKLDGSLDEYLSLQEQLTDVEKLQGKLLEEIEFLE
  GAEGVDHPSHTLQHRYSEHTQLQTQQRAVQEAIQVKLNEFEQWITHYQAAFNNLEATQLA
  SLLQEISTQMDLGPPSYVPATAFLQNAGQAHLISQCEQLEGEVGALLQQRRSVLRGCLEQ
  LHHYATVALQYPKAIFQKHRIEQWKTWMEELICNTTVERCQELYRKYEMQYAPQPPPTVC
  QFITATEMTLQRYAADINSRLIRQVERLKQEAVTVPVCEDQLKEIERCIKVFLHENGEEG
  SLSLASVIISALCTLTRRNLMMEGAASSAGEQLVDLTSRDGAWFLEELCSMSGNVTCLVQ
  LLKQCHLVPQDLDIPNPMEASETVHLANGVYTSLQELNSNFRQIIFPEALRCLMKGEYTL
  ESMLHELDGLIEQTTDGVPLQTLVESLQAYLRNAAMGLEEETHAHYIDVARLLHAQYGEL
  IQPRNGSVDETPKMSAGQMLLVAFDGMFAQVETAFSLLVEKLNKMEIPIAWRKIDIIREA
  RSTQVNFFDDDNHRQVLEEIFFLKRLQTIKEFFRLCGTFSKTLSGSSSLEDQNTVNGPVQ
  IVNVKTLFRNSCFSEDQMAKPIKAFTADFVRQLLIGLPNQALGLTLCSFISALGVDIIAQ
  VEAKDFGAESKVSVDDLCKKAVEHNIQIGKFSQLVMNRATVLASSYDTAWKKHDLVRRLE
  TSISSCKTSLQRVQLHIAMFQWQHEDLLINRPQAMSVTPPPRSAILTSMKKKLHTLSQIE
  TSIATVQEKLAALESSIEQRLKWAGGANPALAPVLQDFEATIAERRNLVLKESQRASQVT
  FLCSNIIHFESLRTRTAEALNLDAALFELIKRCQQMCSFASQFNSSVSELELRLLQRVDT
  GLEHPIGSSEWLLSAHKQLTQDMSTQRAIQTEKEQQIETVCETIQNLVDNIKTVLTGHNR
  QLGDVKHLLKAMAKDEEAALADGEDVPYENSVRQFLGEYKSWQDNIQTVLFTLVQAMGQV
  RSQEHVEMLQEITPTLKELKTQSQSIYNNLVSFASPLVTDATNECSSPTSSATYQPSFAA
  AVRSNTGQKTQPDVMSQNARKLIQKNLATSADTPPSTVPGTGKSVACSPKKAVRDPKTGK
  AVQERNSYAVSVWKRVKAKLEGRDVDPNRRMSVAEQVDYVIKEATNLDNLAQLYEGWTAW
  V
• Function: Serine/threonine protein kinase involved in both mRNA surveillance and genotoxic stress response pathways. Recognizes the substrate consensus sequence [ST]-Q. Plays a central role in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by phosphorylating UPF1/RENT1. Recruited by release factors to stalled ribosomes together with SMG8 and SMG9 (forming the SMG1C protein kinase complex), and UPF1 to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Also acts as a genotoxic stress-activated protein kinase that displays some functional overlap with ATM. Can phosphorylate p53/TP53 and is required for optimal p53/TP53 activation after cellular exposure to genotoxic stress. Its depletion leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). May activate PRKCI but not PRKCZ.
• Tissue Specificity: Widely expressed, with highest level in heart and skeletal muscle. Expressed in placenta, brain, lung and spleen, but not in liver.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway: Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[8]
Hyperthyroidism	DISX87ZH	Strong	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Scleroderma	DISVQ342	Strong	Biomarker	[15]
Skin disease	DISDW8R6	Strong	Biomarker	[15]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[15]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[16]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Altered Expression	[17]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[18]
Breast cancer	DIS7DPX1	moderate	Biomarker	[19]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[19]
Hepatitis C virus infection	DISQ0M8R	moderate	Biomarker	[20]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[21]
Pancreatic adenocarcinoma	DISKHX7S	moderate	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[23]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[24]
Arthritis	DIST1YEL	Disputed	Biomarker	[25]
Cerebral infarction	DISR1WNP	Disputed	Biomarker	[26]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[26]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[27]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[28]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[27]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[29]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[30]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[31]
Pancreatic cancer	DISJC981	Limited	Biomarker	[22]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[29]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[32]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[16]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Serine/threonine-protein kinase SMG1 (SMG1) decreases the response to substance of Gemcitabine.	[46]
Josamycin	DMKJ8LB	Approved	Serine/threonine-protein kinase SMG1 (SMG1) affects the response to substance of Josamycin.	[47]

13 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 Serine/threonine-protein kinase SMG1 (SMG1).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[38]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[39]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[43]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Serine/threonine-protein kinase SMG1 (SMG1).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase SMG1 (SMG1).	[41]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein kinase SMG1 (SMG1).	[41]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Serine/threonine-protein kinase SMG1 (SMG1).	[44]

References

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