Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT511XD9)

• DOT Name: Kinesin-like protein KIF21A (KIF21A)
• Synonyms: Kinesin-like protein KIF2; Renal carcinoma antigen NY-REN-62
• Gene Name: KIF21A
• Related Disease:
  Congenital fibrosis of extraocular muscles
  Congenital fibrosis of extraocular muscles type 1
  Advanced cancer
  Aniridia
  Cleft palate
  Coloboma
  Disease of orbital part of eye adnexa
  Duane retraction syndrome
  Fibrosis of extraocular muscles, congenital, 2
  Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
  Fibrosis of extraocular muscles, congenital, 5
  Isolated cleft palate
  Matthew-Wood syndrome
  Mobius syndrome
  Myopathy
  Neoplasm
  Ocular motility disease
  Schizophrenia
  Spinal stenosis
  Small-cell lung cancer
  Neurodevelopmental disorder
  Ptosis
• UniProt ID: KI21A_HUMAN
• PDB ID: 5D3A; 5NFD; 5YBU; 5YBV; 7KLJ
• Pfam ID: PF00225 ; PF00400
• Sequence:
  MLGAPDESSVRVAVRIRPQLAKEKIEGCHICTSVTPGEPQVFLGKDKAFTFDYVFDIDSQ
  QEQIYIQCIEKLIEGCFEGYNATVFAYGQTGAGKTYTMGTGFDVNIVEEELGIISRAVKH
  LFKSIEEKKHIAIKNGLPAPDFKVNAQFLELYNEEVLDLFDTTRDIDAKSKKSNIRIHED
  STGGIYTVGVTTRTVNTESEMMQCLKLGALSRTTASTQMNVQSSRSHAIFTIHVCQTRVC
  PQIDADNATDNKIISESAQMNEFETLTAKFHFVDLAGSERLKRTGATGERAKEGISINCG
  LLALGNVISALGDKSKRATHVPYRDSKLTRLLQDSLGGNSQTIMIACVSPSDRDFMETLN
  TLKYANRARNIKNKVMVNQDRASQQINALRSEITRLQMELMEYKTGKRIIDEEGVESIND
  MFHENAMLQTENNNLRVRIKAMQETVDALRSRITQLVSDQANHVLARAGEGNEEISNMIH
  SYIKEIEDLRAKLLESEAVNENLRKNLTRATARAPYFSGSSTFSPTILSSDKETIEIIDL
  AKKDLEKLKRKEKRKKKRLQKLEESNREERSVAGKEDNTDTDQEKKEEKGVSERENNELE
  VEESQEVSDHEDEEEEEEEEEDDIDGGESSDESDSESDEKANYQADLANITCEIAIKQKL
  IDELENSQKRLQTLKKQYEEKLMMLQHKIRDTQLERDQVLQNLGSVESYSEEKAKKVRSE
  YEKKLQAMNKELQRLQAAQKEHARLLKNQSQYEKQLKKLQQDVMEMKKTKVRLMKQMKEE
  QEKARLTESRRNREIAQLKKDQRKRDHQLRLLEAQKRNQEVVLRRKTEEVTALRRQVRPM
  SDKVAGKVTRKLSSSDAPAQDTGSSAAAVETDASRTGAQQKMRIPVARVQALPTPATNGN
  RKKYQRKGLTGRVFISKTARMKWQLLERRVTDIIMQKMTISNMEADMNRLLKQREELTKR
  REKLSKRREKIVKENGEGDKNVANINEEMESLTANIDYINDSISDCQANIMQMEEAKEEG
  ETLDVTAVINACTLTEARYLLDHFLSMGINKGLQAAQKEAQIKVLEGRLKQTEITSATQN
  QLLFHMLKEKAELNPELDALLGHALQDLDSVPLENVEDSTDEDAPLNSPGSEGSTLSSDL
  MKLCGEVKPKNKARRRTTTQMELLYADSSELASDTSTGDASLPGPLTPVAEGQEIGMNTE
  TSGTSAREKELSPPPGLPSKIGSISRQSSLSEKKIPEPSPVTRRKAYEKAEKSKAKEQKH
  SDSGTSEASLSPPSSPPSRPRNELNVFNRLTVSQGNTSVQQDKSDESDSSLSEVHRSSRR
  GIINPFPASKGIRAFPLQCIHIAEGHTKAVLCVDSTDDLLFTGSKDRTCKVWNLVTGQEI
  MSLGGHPNNVVSVKYCNYTSLVFTVSTSYIKVWDIRDSAKCIRTLTSSGQVTLGDACSAS
  TSRTVAIPSGENQINQIALNPTGTFLYAASGNAVRMWDLKRFQSTGKLTGHLGPVMCLTV
  DQISSGQDLIITGSKDHYIKMFDVTEGALGTVSPTHNFEPPHYDGIEALTIQGDNLFSGS
  RDNGIKKWDLTQKDLLQQVPNAHKDWVCALGVVPDHPVLLSGCRGGILKVWNMDTFMPVG
  EMKGHDSPINAICVNSTHIFTAADDRTVRIWKARNLQDGQISDTGDLGEDIASN
• Function: Microtubule-binding motor protein probably involved in neuronal axonal transport. In vitro, has a plus-end directed motor activity.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  Kinesins (R-HSA-983189)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital fibrosis of extraocular muscles	DISE84PU	Definitive	Autosomal dominant	[1]
Congenital fibrosis of extraocular muscles type 1	DISQ4HP6	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Aniridia	DIS1P333	Strong	Genetic Variation	[4]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[5]
Coloboma	DISP39N5	Strong	Biomarker	[6]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[7]
Duane retraction syndrome	DISOEBK2	Strong	Biomarker	[8]
Fibrosis of extraocular muscles, congenital, 2	DISHBITM	Strong	Biomarker	[9]
Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement	DISPG5B0	Strong	Biomarker	[9]
Fibrosis of extraocular muscles, congenital, 5	DISCP5U8	Strong	Biomarker	[9]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[10]
Mobius syndrome	DIS9YXP5	Strong	Genetic Variation	[11]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Ocular motility disease	DISEEIHX	Strong	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[12]
Spinal stenosis	DISRONZE	Strong	Biomarker	[13]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[14]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[15]
Ptosis	DISJZNIY	Limited	Genetic Variation	[16]

13 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 Kinesin-like protein KIF21A (KIF21A).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kinesin-like protein KIF21A (KIF21A).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinesin-like protein KIF21A (KIF21A).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kinesin-like protein KIF21A (KIF21A).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[24]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Kinesin-like protein KIF21A (KIF21A).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Kinesin-like protein KIF21A (KIF21A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Kinesin-like protein KIF21A (KIF21A).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[30]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Kinesin-like protein KIF21A (KIF21A).	[31]

3 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 increases the methylation of Kinesin-like protein KIF21A (KIF21A).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Kinesin-like protein KIF21A (KIF21A).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Kinesin-like protein KIF21A (KIF21A).	[28]

References

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• [2] Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients. Ophthalmic Genet. 2004 Dec;25(4):241-6. doi: 10.1080/13816810490902828.
• [3] Prognostic significance of KIF2A and KIF20A expression in human cancer: A systematic review and meta-analysis.Medicine (Baltimore). 2019 Nov;98(46):e18040. doi: 10.1097/MD.0000000000018040.
• [4] Inherited KIF21A and PAX6 gene mutations in a boy with congenital fibrosis of extraocular muscles and aniridia.BMC Med Genet. 2013 Jun 21;14:63. doi: 10.1186/1471-2350-14-63.
• [5] Phenotype-genotype correlation in two patients with 12q proximal deletion.J Hum Genet. 2004;49(5):282-4. doi: 10.1007/s10038-004-0144-5.
• [6] Congenital fibrosis of the extraocular muscles type 1, distinctive conjunctival changes and intrapapillary disc colobomata.Ophthalmic Genet. 2009 Jun;30(2):91-5. doi: 10.1080/13816810802697473.
• [7] Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital fibrosis of extraocular muscles due to mutations in KIF21A.Invest Ophthalmol Vis Sci. 2005 Feb;46(2):530-9. doi: 10.1167/iovs.04-1125.
• [8] Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations.Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4600-11. doi: 10.1167/iovs.10-5438. Epub 2010 Apr 14.
• [9] Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.Neuron. 2014 Apr 16;82(2):334-49. doi: 10.1016/j.neuron.2014.02.038. Epub 2014 Mar 20.
• [10] Prognostic value of Kinesin-4 family genes mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy.Cancer Med. 2019 Nov;8(15):6487-6502. doi: 10.1002/cam4.2524. Epub 2019 Sep 6.
• [11] A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Mbius syndrome.Mol Vis. 2014 Mar 28;20:368-75. eCollection 2014.
• [12] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [13] A Japanese family with FEOM1-linked congenital fibrosis of the extraocular muscles type 1 associated with spinal canal stenosis and refinement of the FEOM1 critical region.Neuromuscul Disord. 2003 Aug;13(6):472-8. doi: 10.1016/s0960-8966(03)00065-8.
• [14] Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.
• [15] Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex.Elife. 2019 Nov 13;8:e50319. doi: 10.7554/eLife.50319.
• [16] Unexpected clinical involvement of hereditary total leuconychia with congenital fibrosis of the extraocular muscles in three generations.Clin Exp Dermatol. 2009 Dec;34(8):e570-2. doi: 10.1111/j.1365-2230.2009.03246.x. Epub 2009 Jun 1.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] 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.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
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• [28] 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.
• [29] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.