Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK8PV0S)

• DOT Name: SH3 and multiple ankyrin repeat domains protein 1 (SHANK1)
• Synonyms: Shank1; Somatostatin receptor-interacting protein; SSTR-interacting protein; SSTRIP
• Gene Name: SHANK1
• Related Disease:
  Anxiety disorder
  Nervous system disease
  Alzheimer disease
  Autism
  Autism spectrum disorder
  Bronchopulmonary dysplasia
  Clear cell renal carcinoma
  Fragile X syndrome
  Papillary renal cell carcinoma
  Pervasive developmental disorder
  Psychotic disorder
  Renal cell carcinoma
  Anxiety
  Intellectual disability
  Post-traumatic stress disorder
  Schizophrenia
• UniProt ID: SHAN1_HUMAN
• PDB ID: 6CPI; 6YWZ; 6YX0; 6YX1; 6YX2; 7A00
• Pfam ID: PF12796 ; PF17820 ; PF00536 ; PF07653
• Sequence:
  MTHSPATSEDEERHSASECPEGGSESDSSPDGPGRGPRGTRGQGSGAPGSLASVRGLQGR
  SMSVPDDAHFSMMVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLF
  QPATSGRDANFLEEERLLREYPQSFEKGVPYLEFRYKTRVYKQTNLDEKQLAKLHTKTGL
  KKFLEYVQLGTSDKVARLLDKGLDPNYHDSDSGETPLTLAAQTEGSVEVIRTLCLGGAHI
  DFRARDGMTALHKAACARHCLALTALLDLGGSPNYKDRRGLTPLFHTAMVGGDPRCCELL
  LFNRAQLGIADENGWQEIHQACQRGHSQHLEHLLFYGAEPGAQNASGNTALHICALYNKE
  TCARILLYRGADKDVKNNNGQTPFQVAVIAGNFELGELIRNHREQDVVPFQESPKYAARR
  RGPPGTGLTVPPALLRANSDTSMALPDWMVFSAPGAASSGAPGPTSGSQGQSQPSAPTTK
  LSSGTLRSASSPRGARARSPSRGRHPEDAKRQPRGRPSSSGTPREGPAGGTGGSGGPGGS
  LGSRGRRRKLYSAVPGRSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRV
  GWFPSDCLEEVANRSQESKQESRSDKAKRLFRHYTVGSYDSFDAPSLMDGIGPGSDYIIK
  EKTVLLQKKDSEGFGFVLRGAKAQTPIEEFTPTPAFPALQYLESVDEGGVAWRAGLRMGD
  FLIEVNGQNVVKVGHRQVVNMIRQGGNTLMVKVVMVTRHPDMDEAVHKKAPQQAKRLPPP
  TISLRSKSMTSELEEMEYEQQPAPVPSMEKKRTVYQMALNKLDEILAAAQQTISASESPG
  PGGLASLGKHRPKGFFATESSFDPHHRAQPSYERPSFLPPGPGLMLRQKSIGAAEDDRPY
  LAPPAMKFSRSLSVPGSEDIPPPPTTSPPEPPYSTPPVPSSSGRLTPSPRGGPFNPGSGG
  PLPASSPASFDGPSPPDTRVGSREKSLYHSGPLPPAHHHPPHHHHHHAPPPQPHHHHAHP
  PHPPEMETGGSPDDPPPRLALGPQPSLRGWRGGGPSPTPGAPSPSHHGSAGGGGGSSQGP
  ALRYFQLPPRAASAAMYVPARSGRGRKGPLVKQTKVEGEPQKGGGLPPAPSPTSPASPQP
  PPAVAAPSEKNSIPIPTIIIKAPSTSSSGRSSQGSSTEAEPPTQPEPTGGGGGGGSSPSP
  APAMSPVPPSPSPVPTPASPSGPATLDFTSQFGAALVGAARREGGWQNEARRRSTLFLST
  DAGDEDGGDGGLGTGAAPGPRLRHSKSIDEGMFSAEPYLRLESAGSGAGYGGYGAGSRAY
  GGGGGSSAFTSFLPPRPLVHPLTGKALDPASPLGLALAARERALKESSEGGGAPQPPPRP
  PSPRYEAPPPTPHHHSPHAHHEPVLRLWGASPPDPARRELGYRAGLGSQEKSLPASPPAA
  RRSLLHRLPPTAPGVGPLLLQLGTEPPAPHPGVSKPWRSAAPEEPERLPLHVRFLENCQP
  RAPVTSGRGPPSEDGPGVPPPSPRRSVPPSPTSPRASEENGLPLLVLPPPAPSVDVEDGE
  FLFVEPLPPPLEFSNSFEKPESPLTPGPPHPLPDTPAPATPLPPVPPPAVAAAPPTLDST
  ASSLTSYDSEVATLTQGASAAPGDPHPPGPPAPAAPAPAAPQPGPDPPPGTDSGIEEVDS
  RSSSDHPLETISSASTLSSLSAEGGGSAGGGGGAGAGVASGPELLDTYVAYLDGQAFGGS
  STPGPPYPPQLMTPSKLRGRALGASGGLRPGPSGGLRDPVTPTSPTVSVTGAGTDGLLAL
  RACSGPPTAGVAGGPVAVEPEVPPVPLPTASSLPRKLLPWEEGPGPPPPPLPGPLAQPQA
  SALATVKASIISELSSKLQQFGGSSAAGGALPWARGGSGGGGDSHHGGASYVPERTSSLQ
  RQRLSDDSQSSLLSKPVSSLFQNWPKPPLPPLPTGTGVSPTAAAAPGATSPSASSSSTST
  RHLQGVEFEMRPPLLRRAPSPSLLPASEHKVSPAPRPSSLPILPSGPLYPGLFDIRGSPT
  GGAGGSADPFAPVFVPPHPGISGGLGGALSGASRSLSPTRLLSLPPDKPFGAKPLGFWTK
  FDVADWLEWLGLAEHRAQFLDHEIDGSHLPALTKEDYVDLGVTRVGHRMNIDRALKFFLE
  R
• Function: Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.
• Tissue Specificity: Expressed in brain particularly in the amygdala, hippocampus, substantia nigra and thalamus. Isoform 2 seems to be expressed ubiquitously.
• KEGG Pathway: Glutamatergic sy.pse (hsa04724)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety disorder	DISBI2BT	Definitive	Biomarker	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Autosomal dominant	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Fragile X syndrome	DISE8W3A	Strong	Altered Expression	[8]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[5]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Anxiety	DISIJDBA	Limited	Biomarker	[1]
Intellectual disability	DISMBNXP	Limited	Biomarker	[10]
Post-traumatic stress disorder	DISHL1EY	Limited	Altered Expression	[11]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[17]

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 decreases the methylation of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1).	[15]

References

• [1] The emerging role of SHANK genes in neuropsychiatric disorders.Dev Neurobiol. 2014 Feb;74(2):113-22. doi: 10.1002/dneu.22128. Epub 2013 Oct 7.
• [2] Neocortical SHANK1 regulation of forebrain dependent associative learning.Neurobiol Learn Mem. 2018 Nov;155:173-179. doi: 10.1016/j.nlm.2018.07.009. Epub 2018 Jul 24.
• [3] Progressive accumulation of amyloid-beta oligomers in Alzheimer's disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins.FEBS J. 2010 Jul;277(14):3051-67. doi: 10.1111/j.1742-4658.2010.07719.x. Epub 2010 Jun 22.
• [4] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [5] SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age.Autism Res. 2019 Mar;12(3):375-383. doi: 10.1002/aur.2065. Epub 2019 Jan 10.
• [6] Reduced Efficacy of d-Amphetamine and 3,4-Methylenedioxymethamphetamine in Inducing Hyperactivity in Mice Lacking the Postsynaptic Scaffolding Protein SHANK1.Front Mol Neurosci. 2018 Nov 16;11:419. doi: 10.3389/fnmol.2018.00419. eCollection 2018.
• [7] Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.Nat Genet. 2011 Dec 4;44(1):17-9. doi: 10.1038/ng.1014.
• [8] Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation.Sci China Life Sci. 2016 Nov;59(11):1093-1105. doi: 10.1007/s11427-016-0194-6. Epub 2016 Oct 11.
• [9] A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.Eur Arch Psychiatry Clin Neurosci. 2012 Mar;262(2):117-24. doi: 10.1007/s00406-011-0233-3. Epub 2011 Sep 7.
• [10] SHANK1 Deletions in Males with Autism Spectrum Disorder.Am J Hum Genet. 2012 May 4;90(5):879-87. doi: 10.1016/j.ajhg.2012.03.017. Epub 2012 Apr 12.
• [11] Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence.Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8390-8395. doi: 10.1073/pnas.1701749114. Epub 2017 Jul 17.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.