Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT35570Y)

• DOT Name: Kinesin heavy chain isoform 5C (KIF5C)
• Synonyms: EC 3.6.4.-; Kinesin heavy chain neuron-specific 2; Kinesin-1
• Gene Name: KIF5C
• Related Disease:
  Adult glioblastoma
  Complex cortical dysplasia with other brain malformations 2
  Glioblastoma multiforme
  Hereditary spastic paraplegia 10
  Intellectual disability
  Isolated congenital microcephaly
  Macular corneal dystrophy
  Microlissencephaly
  Neoplasm
  Pure hereditary spastic paraplegia
  Vascular purpura
  Epilepsy
  Neurodevelopmental disorder
  Hereditary spastic paraplegia
• UniProt ID: KIF5C_HUMAN
• EC Number: 3.6.4.-
• Pfam ID: PF00225
• Sequence:
  MADPAECSIKVMCRFRPLNEAEILRGDKFIPKFKGDETVVIGQGKPYVFDRVLPPNTTQE
  QVYNACAKQIVKDVLEGYNGTIFAYGQTSSGKTHTMEGKLHDPQLMGIIPRIAHDIFDHI
  YSMDENLEFHIKVSYFEIYLDKIRDLLDVSKTNLAVHEDKNRVPYVKGCTERFVSSPEEV
  MDVIDEGKANRHVAVTNMNEHSSRSHSIFLINIKQENVETEKKLSGKLYLVDLAGSEKVS
  KTGAEGAVLDEAKNINKSLSALGNVISALAEGTKTHVPYRDSKMTRILQDSLGGNCRTTI
  VICCSPSVFNEAETKSTLMFGQRAKTIKNTVSVNLELTAEEWKKKYEKEKEKNKTLKNVI
  QHLEMELNRWRNGEAVPEDEQISAKDQKNLEPCDNTPIIDNIAPVVAGISTEEKEKYDEE
  ISSLYRQLDDKDDEINQQSQLAEKLKQQMLDQDELLASTRRDYEKIQEELTRLQIENEAA
  KDEVKEVLQALEELAVNYDQKSQEVEDKTRANEQLTDELAQKTTTLTTTQRELSQLQELS
  NHQKKRATEILNLLLKDLGEIGGIIGTNDVKTLADVNGVIEEEFTMARLYISKMKSEVKS
  LVNRSKQLESAQMDSNRKMNASERELAACQLLISQHEAKIKSLTDYMQNMEQKRRQLEES
  QDSLSEELAKLRAQEKMHEVSFQDKEKEHLTRLQDAEEMKKALEQQMESHREAHQKQLSR
  LRDEIEEKQKIIDEIRDLNQKLQLEQEKLSSDYNKLKIEDQEREMKLEKLLLLNDKREQA
  REDLKGLEETVSRELQTLHNLRKLFVQDLTTRVKKSVELDNDDGGGSAAQKQKISFLENN
  LEQLTKVHKQLVRDNADLRCELPKLEKRLRATAERVKALESALKEAKENAMRDRKRYQQE
  VDRIKEAVRAKNMARRAHSAQIAKPIRPGHYPASSPTAVHAIRGGGGSSSNSTHYQK
• Function: Microtubule-associated force-producing protein that may play a role in organelle transport. Has ATPase activity. Involved in synaptic transmission. Mediates dendritic trafficking of mRNAs. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation.
• Tissue Specificity: Highest expression in brain, prostate and testis, and moderate expression in kidney, small intestine and ovary.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Dopaminergic sy.pse (hsa04728)
  Motor proteins (hsa04814)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway: Insulin processing (R-HSA-264876)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Complex cortical dysplasia with other brain malformations 2	DIS9Q9XU	Strong	Autosomal dominant	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Hereditary spastic paraplegia 10	DISYFO3L	Strong	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[2]
Macular corneal dystrophy	DISOLD0H	Strong	Genetic Variation	[5]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Biomarker	[7]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[8]
Epilepsy	DISBB28L	moderate	Genetic Variation	[5]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[5]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[9]

19 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 Kinesin heavy chain isoform 5C (KIF5C).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[17]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[17]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[17]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Kinesin heavy chain isoform 5C (KIF5C).	[25]

2 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 heavy chain isoform 5C (KIF5C).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Kinesin heavy chain isoform 5C (KIF5C).	[22]

References

• [1] Differential display of messenger ribonucleic acid: a useful technique for analyzing differential gene expression in human brain tumors.Neurosurgery. 1995 Sep;37(3):464-9; discussion 469-70. doi: 10.1227/00006123-199509000-00014.
• [2] Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet. 2013 Jun;45(6):639-47. doi: 10.1038/ng.2613. Epub 2013 Apr 21.
• [3] A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).Am J Hum Genet. 2002 Nov;71(5):1189-94. doi: 10.1086/344210. Epub 2002 Sep 24.
• [4] Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function. J Med Genet. 2014 Jul;51(7):487-94. doi: 10.1136/jmedgenet-2013-102182. Epub 2014 May 8.
• [5] Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development.Am J Med Genet A. 2017 Dec;173(12):3127-3131. doi: 10.1002/ajmg.a.38496. Epub 2017 Oct 19.
• [6] Reduced miR-203 predicts metastasis and poor survival in esophageal carcinoma.Aging (Albany NY). 2019 Dec 16;11(24):12114-12130. doi: 10.18632/aging.102543. Epub 2019 Dec 16.
• [7] Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia.Neurology. 2004 Sep 28;63(6):1108-10. doi: 10.1212/01.wnl.0000138731.60693.d2.
• [8] Three routes to suppression of the neurodegenerative phenotypes caused by kinesin heavy chain mutations.Genetics. 2012 Sep;192(1):173-83. doi: 10.1534/genetics.112.140798. Epub 2012 Jun 19.
• [9] SPG10 is a rare cause of spastic paraplegia in European families.J Neurol Neurosurg Psychiatry. 2008 May;79(5):584-7. doi: 10.1136/jnnp.2007.137596. Epub 2008 Feb 1.
• [10] Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [16] 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.
• [17] 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.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] 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.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.