Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX26906)

• DOT Name: Protein sidekick-1 (SDK1)
• Gene Name: SDK1
• Related Disease:
  Autism
  Anxiety disorder
  Focal segmental glomerulosclerosis
  Gastroesophageal reflux disease
  Hepatocellular carcinoma
  High blood pressure
  Motion sickness
  Narcolepsy
  Primary biliary cholangitis
• UniProt ID: SDK1_HUMAN
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MARGARPSAAGGGGGGAEPPERAGPGRPRGSPPGRARPSLAPRPGPEPSRPRAAPETSGG
  DTAGAGRCGGRRAAKLGPGRRGWWALLALQLHLLRALAQDDVAPYFKTEPGLPQIHLEGN
  RLVLTCLAEGSWPLEFKWMRDDSELTTYSSEYKYIIPSLQKLDAGFYRCVVRNRMGALLQ
  RKSEVQVAYMGSFMDTDQRKTVSQGRAAILNLLPITSYPRPQVTWFREGHKIIPSNRIAI
  TLENQLVILATTTSDAGAYYVQAVNEKNGENKTSPFIHLSIARDVGTPETMAPTIVVPPG
  NRSVVAGSSETTLECIASARPVEDLSVTWKRNGVRITSGLHSFGRRLTISNPTSADTGPY
  VCEAALPGSAFEPARATAFLFIIEPPYFTAEPESRISAEVEETVDIGCQAMGVPLPTLQW
  YKDAISISRLQNPRYKVLASGGLRIQKLRPEDSGIFQCFASNEGGEIQTHTYLDVTNIAP
  VFTQRPVDTTVTDGMTAILRCEVSGAPKPAITWKRENHILASGSVRIPRFMLLESGGLQI
  APVFIQDAGNYTCYAANTEGSLNASATLTVWNRTSIVHPPEDHVVIKGTTATLHCGATHD
  PRVSLRYVWKKDNVALTPSSTSRIVVEKDGSLLISQTWSGDIGDYSCEIVSEGGNDSRMA
  RLEVIELPHSPQNLLVSPNSSHSHAVVLSWVRPFDGNSPILYYIVELSENNSPWKVHLSN
  VGPEMTGVTVSGLTPARTYQFRVCAVNEVGRGQYSAETSRLMLPEEPPSAPPKNIVASGR
  TNQSIMVQWQPPPETEHNGVLRGYILRYRLAGLPGEYQQRNITSPEVNYCLVTDLIIWTQ
  YEIQVAAYNGAGLGVFSRAVTEYTLQGVPTAPPQNVQTEAVNSTTIQFLWNPPPQQFING
  INQGYKLLAWPADAPEAVTVVTIAPDFHGVHHGHITNLKKFTAYFTSVLCFTTPGDGPPS
  TPQLVWTQEDKPGAVGHLSFTEILDTSLKVSWQEPLEKNGIITGYQISWEVYGRNDSRLT
  HTLNSTTHEYKIQGLSSLTTYTIDVAAVTAVGTGLVTSSTISSGVPPDLPGAPSNLVISN
  ISPRSATLQFRPGYDGKTSISRWIVEGQVGAIGDEEEWVTLYEEENEPDAQMLEIPNLTP
  YTHYRFRMKQVNIVGPSPYSPSSRVIQTLQAPPDVAPTSVTVRTASETSLRLRWVPLPDS
  QYNGNPESVGYRIKYWRSDLQSSAVAQVVSDRLEREFTIEELEEWMEYELQMQAFNAVGA
  GPWSEVVRGRTRESVPSAAPENVSAEAVSSTQILLTWTSVPEQDQNGLILGYKILFRAKD
  LDPEPRSHIVRGNHTQSALLAGLRKFVLYELQVLAFTRIGNGVPSTPLILERTKDDAPGP
  PVRLVFPEVRLTSVRIVWQPPEEPNGIILGYQIAYRLASSSPHTFTTVEVGATVRQFTAT
  DLAPESAYIFRLSAKTRQGWGEPLEATVITTEKRERPAPPRELLVPQAEVTARSLRLQWV
  PGSDGASPIRYFTMQVRELPRGEWQTYSSSISHEATACVVDRLRPFTSYKLRLKATNDIG
  DSDFSSETEAVTTLQDVPGEPPGSVSATPHTTSSVLIQWQPPRDESLNGLLQGYRIYYRE
  LEYEAGSGTEAKTLKNPIALHAELTAQSSFKTVNSSSTSTMCELTHLKKYRRYEVIMTAY
  NIIGESPASAPVEVFVGEAAPAMAPQNVQVTPLTASQLEVTWDPPPPESQNGNIQGYKIY
  YWEADSQNETEKMKVLFLPEPVVRLKNLTSHTKYLVSISAFNAAGDGPKSDPQQGRTHQA
  APGAPSFLAFSEITSTTLNVSWGEPAAANGILQGYRVVYEPLAPVQGVSKVVTVEVRGNW
  QRWLKVRDLTKGVTYFFRVQARTITYGPELQANITAGPAEGSPGSPRDVLVTKSASELTL
  QWTEGHSGDTPTTGYVIEARPSDEGLWDMFVKDIPRSATSYTLSLDKLRQGVTYEFRVVA
  VNEAGYGEPSNPSTAVSAQVEAPFYEEWWFLLVMALSSLIVILLVVFALVLHGQNKKYKN
  CSTGKGISTMEESVTLDNGGFAALELSSRHLNVKSTFSKKNGTRSPPRPSPGGLHYSDED
  ICNKYNGAVLTESVSLKEKSADASESEATDSDYEDALPKHSFVNHYMSDPTYYNSWKRRA
  QGRAPAPHRYEAVAGSEAGAQLHPVITTQSAGGVYTPAGPGARTPLTGFSSFV
• Function: Adhesion molecule that promotes lamina-specific synaptic connections in the retina. Expressed in specific subsets of interneurons and retinal ganglion cells (RGCs) and promotes synaptic connectivity via homophilic interactions.
• Tissue Specificity: Up-regulated in glomeruli in HIV-associated nephropathy. In diseased glomeruli, significantly overexpressed and the expression is no longer restricted to mesangial cells but includes podocytes and parietal epithelial cells .
• Reactome Pathway: SDK interactions (R-HSA-373756)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[2]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[3]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[7]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[8]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[9]

7 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 Protein sidekick-1 (SDK1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein sidekick-1 (SDK1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein sidekick-1 (SDK1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein sidekick-1 (SDK1).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein sidekick-1 (SDK1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protein sidekick-1 (SDK1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Protein sidekick-1 (SDK1).	[17]

3 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 Protein sidekick-1 (SDK1).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein sidekick-1 (SDK1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Protein sidekick-1 (SDK1).	[16]

References

• [1] A genome-wide association study of autism incorporating autism diagnostic interview-revised, autism diagnostic observation schedule, and social responsiveness scale.Child Dev. 2013 Jan-Feb;84(1):17-33. doi: 10.1111/j.1467-8624.2012.01838.x. Epub 2012 Aug 30.
• [2] Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study.JAMA Psychiatry. 2019 Sep 1;76(9):924-932. doi: 10.1001/jamapsychiatry.2019.1119.
• [3] Up-regulation of the homophilic adhesion molecule sidekick-1 in podocytes contributes to glomerulosclerosis.J Biol Chem. 2010 Aug 13;285(33):25677-85. doi: 10.1074/jbc.M110.133959. Epub 2010 Jun 18.
• [4] Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.Nat Commun. 2019 Sep 16;10(1):4219. doi: 10.1038/s41467-019-11968-2.
• [5] Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach.Oncotarget. 2017 Jun 27;8(26):41890-41902. doi: 10.18632/oncotarget.17462.
• [6] Assessment of a polymorphism of SDK1 with hypertension in Japanese Individuals.Am J Hypertens. 2010 Jan;23(1):70-7. doi: 10.1038/ajh.2009.190. Epub 2009 Oct 22.
• [7] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [8] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [9] Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.Am J Hum Genet. 2012 Oct 5;91(4):721-8. doi: 10.1016/j.ajhg.2012.08.010. Epub 2012 Sep 20.
• [10] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.