Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTACUFB2)

• DOT Name: Kinesin light chain 4 (KLC4)
• Synonyms: KLC 4; Kinesin-like protein 8
• Gene Name: KLC4
• Related Disease:
  3-M syndrome
  Cervical cancer
  Cervical carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: KLC4_HUMAN
• Pfam ID: PF13374 ; PF13424
• Sequence:
  MSGLVLGQRDEPAGHRLSQEEILGSTRLVSQGLEALRSEHQAVLQSLSQTIECLQQGGHE
  EGLVHEKARQLRRSMENIELGLSEAQVMLALASHLSTVESEKQKLRAQVRRLCQENQWLR
  DELAGTQQRLQRSEQAVAQLEEEKKHLEFLGQLRQYDEDGHTSEEKEGDATKDSLDDLFP
  NEEEEDPSNGLSRGQGATAAQQGGYEIPARLRTLHNLVIQYAAQGRYEVAVPLCKQALED
  LERTSGRGHPDVATMLNILALVYRDQNKYKEAAHLLNDALSIRESTLGPDHPAVAATLNN
  LAVLYGKRGKYKEAEPLCQRALEIREKVLGTNHPDVAKQLNNLALLCQNQGKYEAVERYY
  QRALAIYEGQLGPDNPNVARTKNNLASCYLKQGKYAEAETLYKEILTRAHVQEFGSVDDD
  HKPIWMHAEEREEMSKSRHHEGGTPYAEYGGWYKACKVSSPTVNTTLRNLGALYRRQGKL
  EAAETLEECALRSRRQGTDPISQTKVAELLGESDGRRTSQEGPGDSVKFEGGEDASVAVE
  WSGDGSGTLQRSGSLGKIRDVLRRSSELLVRKLQGTEPRPSSSNMKRAASLNYLNQPSAA
  PLQVSRGLSASTMDLSSSS
• 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.
• 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)
  Kinesins (R-HSA-983189)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-M syndrome	DISGKJY3	Definitive	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kinesin light chain 4 (KLC4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kinesin light chain 4 (KLC4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin light chain 4 (KLC4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kinesin light chain 4 (KLC4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kinesin light chain 4 (KLC4).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kinesin light chain 4 (KLC4).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Kinesin light chain 4 (KLC4).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinesin light chain 4 (KLC4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinesin light chain 4 (KLC4).	[15]

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 Kinesin light chain 4 (KLC4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Kinesin light chain 4 (KLC4).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Kinesin light chain 4 (KLC4).	[14]

References

• [1] Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.Am J Med Genet A. 2019 Jul;179(7):1157-1172. doi: 10.1002/ajmg.a.61154. Epub 2019 Apr 13.
• [2] SETD3 reduces KLC4 expression to improve the sensitization of cervical cancer cell to radiotherapy.Biochem Biophys Res Commun. 2019 Aug 27;516(3):619-625. doi: 10.1016/j.bbrc.2019.06.058. Epub 2019 Jun 22.
• [3] Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx.Cell Death Dis. 2018 May 1;9(5):496. doi: 10.1038/s41419-018-0549-2.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.