Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQXWJR4)

• DOT Name: Striated muscle preferentially expressed protein kinase (SPEG)
• Synonyms: EC 2.7.11.1; Aortic preferentially expressed protein 1; APEG-1
• Gene Name: SPEG
• Related Disease:
  Myopathy, centronuclear, 5
  Arteriosclerosis
  Cardiac disease
  Cardiac failure
  Congenital myopathy
  Congestive heart failure
  Myopathy, centronuclear, 2
  Neuromuscular disease
  Dilated cardiomyopathy
  Autosomal recessive centronuclear myopathy
  Centronuclear myopathy
• UniProt ID: SPEG_HUMAN
• PDB ID: 1U2H
• EC Number: 2.7.11.1
• Pfam ID: PF07679 ; PF00069 ; PF16650
• Sequence:
  MQKARGTRGEDAGTRAPPSPGVPPKRAKVGAGGGAPVAVAGAPVFLRPLKNAAVCAGSDV
  RLRVVVSGTPQPSLRWFRDGQLLPAPAPEPSCLWLRRCGAQDAGVYSCMAQNERGRASCE
  AVLTVLEVGDSETAEDDISDVQGTQRLELRDDGAFSTPTGGSDTLVGTSLDTPPTSVTGT
  SEEQVSWWGSGQTVLEQEAGSGGGTRRLPGSPRQAQATGAGPRHLGVEPLVRASRANLVG
  ASWGSEDSLSVASDLYGSAFSLYRGRALSIHVSVPQSGLRREEPDLQPQLASEAPRRPAQ
  PPPSKSALLPPPSPRVGKRSPPGPPAQPAATPTSPHRRTQEPVLPEDTTTEEKRGKKSKS
  SGPSLAGTAESRPQTPLSEASGRLSALGRSPRLVRAGSRILDKLQFFEERRRSLERSDSP
  PAPLRPWVPLRKARSLEQPKSERGAPWGTPGASQEELRAPGSVAERRRLFQQKAASLDER
  TRQRSPASDLELRFAQELGRIRRSTSREELVRSHESLRATLQRAPSPREPGEPPLFSRPS
  TPKTSRAVSPAAAQPPSPSSAEKPGDEPGRPRSRGPAGRTEPGEGPQQEVRRRDQFPLTR
  SRAIQECRSPVPPPAADPPEARTKAPPGRKREPPAQAVRFLPWATPGLEGAAVPQTLEKN
  RAGPEAEKRLRRGPEEDGPWGPWDRRGARSQGKGRRARPTSPELESSDDSYVSAGEEPLE
  APVFEIPLQNVVVAPGADVLLKCIITANPPPQVSWHKDGSALRSEGRLLLRAEGERHTLL
  LREARAADAGSYMATATNELGQATCAASLTVRPGGSTSPFSSPITSDEEYLSPPEEFPEP
  GETWPRTPTMKPSPSQNRRSSDTGSKAPPTFKVSLMDQSVREGQDVIMSIRVQGEPKPVV
  SWLRNRQPVRPDQRRFAEEAEGGLCRLRILAAERGDAGFYTCKAVNEYGARQCEARLEVR
  AHPESRSLAVLAPLQDVDVGAGEMALFECLVAGPTDVEVDWLCRGRLLQPALLKCKMHFD
  GRKCKLLLTSVHEDDSGVYTCKLSTAKDELTCSARLTVRPSLAPLFTRLLEDVEVLEGRA
  ARFDCKISGTPPPVVTWTHFGCPMEESENLRLRQDGGLHSLHIAHVGSEDEGLYAVSAVN
  THGQAHCSAQLYVEEPRTAASGPSSKLEKMPSIPEEPEQGELERLSIPDFLRPLQDLEVG
  LAKEAMLECQVTGLPYPTISWFHNGHRIQSSDDRRMTQYRDVHRLVFPAVGPQHAGVYKS
  VIANKLGKAACYAHLYVTDVVPGPPDGAPQVVAVTGRMVTLTWNPPRSLDMAIDPDSLTY
  TVQHQVLGSDQWTALVTGLREPGWAATGLRKGVQHIFRVLSTTVKSSSKPSPPSEPVQLL
  EHGPTLEEAPAMLDKPDIVYVVEGQPASVTVTFNHVEAQVVWRSCRGALLEARAGVYELS
  QPDDDQYCLRICRVSRRDMGALTCTARNRHGTQTCSVTLELAEAPRFESIMEDVEVGAGE
  TARFAVVVEGKPLPDIMWYKDEVLLTESSHVSFVYEENECSLVVLSTGAQDGGVYTCTAQ
  NLAGEVSCKAELAVHSAQTAMEVEGVGEDEDHRGRRLSDFYDIHQEIGRGAFSYLRRIVE
  RSSGLEFAAKFIPSQAKPKASARREARLLARLQHDCVLYFHEAFERRRGLVIVTELCTEE
  LLERIARKPTVCESEIRAYMRQVLEGIHYLHQSHVLHLDVKPENLLVWDGAAGEQQVRIC
  DFGNAQELTPGEPQYCQYGTPEFVAPEIVNQSPVSGVTDIWPVGVVAFLCLTGISPFVGE
  NDRTTLMNIRNYNVAFEETTFLSLSREARGFLIKVLVQDRLRPTAEETLEHPWFKTQAKG
  AEVSTDHLKLFLSRRRWQRSQISYKCHLVLRPIPELLRAPPERVWVTMPRRPPPSGGLSS
  SSDSEEEELEELPSVPRPLQPEFSGSRVSLTDIPTEDEALGTPETGAATPMDWQEQGRAP
  SQDQEAPSPEALPSPGQEPAAGASPRRGELRRGSSAESALPRAGPRELGRGLHKAASVEL
  PQRRSPSPGATRLARGGLGEGEYAQRLQALRQRLLRGGPEDGKVSGLRGPLLESLGGRAR
  DPRMARAASSEAAPHHQPPLENRGLQKSSSFSQGEAEPRGRHRRAGAPLEIPVARLGARR
  LQESPSLSALSEAQPSSPARPSAPKPSTPKSAEPSATTPSDAPQPPAPQPAQDKAPEPRP
  EPVRASKPAPPPQALQTLALPLTPYAQIIQSLQLSGHAQGPSQGPAAPPSEPKPHAAVFA
  RVASPPPGAPEKRVPSAGGPPVLAEKARVPTVPPRPGSSLSSSIENLESEAVFEAKFKRS
  RESPLSLGLRLLSRSRSEERGPFRGAEEEDGIYRPSPAGTPLELVRRPERSRSVQDLRAV
  GEPGLVRRLSLSLSQRLRRTPPAQRHPAWEARGGDGESSEGGSSARGSPVLAMRRRLSFT
  LERLSSRLQRSGSSEDSGGASGRSTPLFGRLRRATSEGESLRRLGLPHNQLAAQAGATTP
  SAESLGSEASATSGSSAPGESRSRLRWGFSRPRKDKGLSPPNLSASVQEELGHQYVRSES
  DFPPVFHIKLKDQVLLEGEAATLLCLPAACPAPHISWMKDKKSLRSEPSVIIVSCKDGRQ
  LLSIPRAGKRHAGLYECSATNVLGSITSSCTVAVARVPGKLAPPEVPQTYQDTALVLWKP
  GDSRAPCTYTLERRVDGESVWHPVSSGIPDCYYNVTHLPVGVTVRFRVACANRAGQGPFS
  NSSEKVFVRGTQDSSAVPSAAHQEAPVTSRPARARPPDSPTSLAPPLAPAAPTPPSVTVS
  PSSPPTPPSQALSSLKAVGPPPQTPPRRHRGLQAARPAEPTLPSTHVTPSEPKPFVLDTG
  TPIPASTPQGVKPVSSSTPVYVVTSFVSAPPAPEPPAPEPPPEPTKVTVQSLSPAKEVVS
  SPGSSPRSSPRPEGTTLRQGPPQKPYTFLEEKARGRFGVVRACRENATGRTFVAKIVPYA
  AEGKRRVLQEYEVLRTLHHERIMSLHEAYITPRYLVLIAESCGNRELLCGLSDRFRYSED
  DVATYMVQLLQGLDYLHGHHVLHLDIKPDNLLLAPDNALKIVDFGSAQPYNPQALRPLGH
  RTGTLEFMAPEMVKGEPIGSATDIWGAGVLTYIMLSGRSPFYEPDPQETEARIVGGRFDA
  FQLYPNTSQSATLFLRKVLSVHPWSRPSLQDCLAHPWLQDAYLMKLRRQTLTFTTNRLKE
  FLGEQRRRRAEAATRHKVLLRSYPGGP
• Function: Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
• Tissue Specificity: Isoform 1 is preferentially expressed in striated muscle. Non-kinase form such as isoform 3 is predominantly expressed in the aorta. Isoform 3 appears to be expressed only in highly differentiated ASMC in normal vessel walls and down-regulated in dedifferentiated ASMC in vivo. In response to vascular injuries ASMC dedifferentiate and change from a quiescent and contractile phenotype to a proliferative and synthetic phenotype. This proliferation of vascular smooth muscle cells is one of the most prominent features of atherosclerosis.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy, centronuclear, 5	DIS3CKAE	Definitive	Autosomal recessive	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Cardiac disease	DISVO1I5	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Myopathy, centronuclear, 2	DIS7NCZX	Strong	GermlineCausalMutation	[6]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[7]
Dilated cardiomyopathy	DISX608J	moderate	Biomarker	[6]
Autosomal recessive centronuclear myopathy	DIS4ZI6X	Supportive	Autosomal recessive	[6]
Centronuclear myopathy	DISXBEJO	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[14]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[15]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Striated muscle preferentially expressed protein kinase (SPEG).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Striated muscle preferentially expressed protein kinase (SPEG).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Striated muscle preferentially expressed protein kinase (SPEG).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Genomic rearrangements on VCAM1, SELE, APEG1and AIF1 loci in atherosclerosis.J Cell Mol Med. 2005 Jan-Mar;9(1):153-9. doi: 10.1111/j.1582-4934.2005.tb00345.x.
• [3] SPEG Controls Calcium Reuptake Into the Sarcoplasmic Reticulum Through Regulating SERCA2a by Its Second Kinase-Domain.Circ Res. 2019 Mar;124(5):712-726. doi: 10.1161/CIRCRESAHA.118.313916.
• [4] SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity.Circ Res. 2017 Jan 6;120(1):110-119. doi: 10.1161/CIRCRESAHA.116.309977. Epub 2016 Oct 11.
• [5] Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.Muscle Nerve. 2019 Mar;59(3):357-362. doi: 10.1002/mus.26378. Epub 2018 Nov 28.
• [6] SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet. 2014 Aug 7;95(2):218-26. doi: 10.1016/j.ajhg.2014.07.004. Epub 2014 Jul 31.
• [7] Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth.Orphanet J Rare Dis. 2015 Nov 17;10:148. doi: 10.1186/s13023-015-0364-0.
• [8] Novel SPEG variant cause centronuclear myopathy in China.J Clin Lab Anal. 2020 Feb;34(2):e23054. doi: 10.1002/jcla.23054. Epub 2019 Oct 18.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] 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.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.