Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSTTTW7)

• DOT Name: Kinesin light chain 1 (KLC1)
• Synonyms: KLC 1
• Gene Name: KLC1
• Related Disease:
  Adenocarcinoma
  Alzheimer disease
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Glioma
  Hereditary motor neuron disease
  Major depressive disorder
  Neuroblastoma
  Multiple sclerosis
  Parkinson disease
  Schizophrenia
• UniProt ID: KLC1_HUMAN
• PDB ID: 3NF1; 5OJ8; 7AI4; 7AIE
• Pfam ID: PF13374 ; PF13424
• Sequence:
  MYDNMSTMVYIKEDKLEKLTQDEIISKTKQVIQGLEALKNEHNSILQSLLETLKCLKKDD
  ESNLVEEKSNMIRKSLEMLELGLSEAQVMMALSNHLNAVESEKQKLRAQVRRLCQENQWL
  RDELANTQQKLQKSEQSVAQLEEEKKHLEFMNQLKKYDDDISPSEDKDTDSTKEPLDDLF
  PNDEDDPGQGIQQQHSSAAAAAQQGGYEIPARLRTLHNLVIQYASQGRYEVAVPLCKQAL
  EDLEKTSGHDHPDVATMLNILALVYRDQNKYKDAANLLNDALAIREKTLGKDHPAVAATL
  NNLAVLYGKRGKYKEAEPLCKRALEIREKVLGKDHPDVAKQLNNLALLCQNQGKYEEVEY
  YYQRALEIYQTKLGPDDPNVAKTKNNLASCYLKQGKFKQAETLYKEILTRAHEREFGSVD
  DENKPIWMHAEEREECKGKQKDGTSFGEYGGWYKACKVDSPTVTTTLKNLGALYRRQGKF
  EAAETLEEAAMRSRKQGLDNVHKQRVAEVLNDPENMEKRRSRESLNVDVVKYESGPDGGE
  EVSMSVEWNGGVSGRASFCGKRQQQQWPGRRHR
• Function: Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport. The light chain may function in coupling of cargo to the heavy chain or in the modulation of its ATPase activity.
• Tissue Specificity: Found in a variety of tissues. Mostly abundant in brain and spine.
• KEGG Pathway:
  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)
• Reactome Pathway:
  RHO GTPases activate KTN1 (R-HSA-5625970)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Kinesins (R-HSA-983189)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hereditary motor neuron disease	DIS6XNI0	Strong	Genetic Variation	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[3]
Multiple sclerosis	DISB2WZI	Disputed	Genetic Variation	[8]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Kinesin light chain 1 (KLC1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kinesin light chain 1 (KLC1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Kinesin light chain 1 (KLC1).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Kinesin light chain 1 (KLC1).	[20]

7 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 light chain 1 (KLC1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinesin light chain 1 (KLC1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinesin light chain 1 (KLC1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Kinesin light chain 1 (KLC1).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Kinesin light chain 1 (KLC1).	[17]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Kinesin light chain 1 (KLC1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Kinesin light chain 1 (KLC1).	[21]

References

• [1] ALK-rearrangement neuroendocrine carcinoma of the lung: a comprehensive study of a rare case series and review of literature.Onco Targets Ther. 2018 Aug 17;11:4991-4998. doi: 10.2147/OTT.S172124. eCollection 2018.
• [2] Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer's disease and regulates axonal transport and processing of the amyloid precursor protein.Acta Neuropathol Commun. 2019 Dec 5;7(1):200. doi: 10.1186/s40478-019-0857-5.
• [3] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid- accumulation modifier.Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2638-43. doi: 10.1073/pnas.1307345111. Epub 2014 Feb 4.
• [4] A role for kinesin-1 subunits KIF5B/KLC1 in regulating epithelial mesenchymal plasticity in breast tumorigenesis.EBioMedicine. 2019 Jul;45:92-107. doi: 10.1016/j.ebiom.2019.06.009. Epub 2019 Jun 14.
• [5] Identification of a novel KLC1-ROS1 fusion in a case of pediatric low-grade localized glioma.Brain Tumor Pathol. 2019 Jan;36(1):14-19. doi: 10.1007/s10014-018-0330-3. Epub 2018 Oct 22.
• [6] The kinesin light chain gene: its mapping and exclusion in mouse and human forms of inherited motor neuron degeneration.Neurosci Lett. 1999 Sep 24;273(1):49-52. doi: 10.1016/s0304-3940(99)00620-5.
• [7] Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.Nat Commun. 2018 Apr 16;9(1):1470. doi: 10.1038/s41467-018-03819-3.
• [8] A cytoskeleton motor protein genetic variant may exert a protective effect on the occurrence of multiple sclerosis: the janus face of the kinesin light-chain 1 56836CC genetic variant.Neuromolecular Med. 2007;9(4):335-9. doi: 10.1007/s12017-007-8014-x. Epub 2007 Oct 13.
• [9] Kinesin light chain 1 gene haplotypes in three conformational diseases.Neuromolecular Med. 2010 Sep;12(3):229-36. doi: 10.1007/s12017-009-8103-0. Epub 2009 Nov 13.
• [10] Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of complex traits and disease.Transl Psychiatry. 2019 Feb 28;9(1):105. doi: 10.1038/s41398-019-0437-2.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] 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.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] 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.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] 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.
• [18] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.