Details of Drug Off-Target (DOT)

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

• DOT Name: Kinesin-like protein KIF18B (KIF18B)
• Gene Name: KIF18B
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Clear cell renal carcinoma
  Cutaneous melanoma
  Melanoma
  Neoplasm
  Lung adenocarcinoma
• UniProt ID: KI18B_HUMAN
• Pfam ID: PF00225
• Sequence:
  MAVEDSTLQVVVRVRPPTPRELDSQRRPVVQVVDERVLVFNPEEPDGGFPGLKWGGTHDG
  PKKKGKDLTFVFDRVFGEAATQQDVFQHTTHSVLDSFLQGYNCSVFAYGATGAGKTHTML
  GREGDPGIMYLTTVELYRRLEARQQEKHFEVLISYQEVYNEQIHDLLEPKGPLAIREDPD
  KGVVVQGLSFHQPASAEQLLEILTRGNRNRTQHPTDANATSSRSHAIFQIFVKQQDRVPG
  LTQAVQVAKMSLIDLAGSERASSTHAKGERLREGANINRSLLALINVLNALADAKGRKTH
  VPYRDSKLTRLLKDSLGGNCRTVMIAAISPSSLTYEDTYNTLKYADRAKEIRLSLKSNVT
  SLDCHISQYATICQQLQAEVAALRKKLQVYEGGGQPPPQDLPGSPKSGPPPEHQPCTPEL
  PAGPRALQEESLGMEAQVERAMEGNSSDQEQSPEDEDEGPAEEVPTQMPEQNPTHALPES
  PRLTLQPKPVVGHFSARELDGDRSKQLALKVLCVAQRQYSLLQAANLLTPDMITEFETLQ
  QLVQEEKIEPGAEALRTSGLARGAPLAQELCSESIPVPSPLCPEPPGYTGPVTRTMARRL
  SGPLHTLGIPPGPNCTPAQGSRWPMEKKRRRPSALEADSPMAPKRGTKRQRQSFLPCLRR
  GSLPDTQPSQGPSTPKGERASSPCHSPRVCPATVIKSRVPLGPSAMQNCSTPLALPTRDL
  NATFDLSEEPPSKPSFHECIGWDKIPQELSRLDQPFIPRAPVPLFTMKGPKPTSSLPGTS
  ACKKKRVASSSVSHGRSRIARLPSSTLKRPAGPLVLPELPLSPLCPSNRRNGKDLIRVGR
  ALSAGNGVTKVS
• Function: In complex with KIF2C, constitutes the major microtubule plus-end depolymerizing activity in mitotic cells. Its major role may be to transport KIF2C and/or MAPRE1 along microtubules.
• Tissue Specificity: Shows a prominent expression in the amygdala.
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Cutaneous melanoma	DIS3MMH9	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Kinesin-like protein KIF18B (KIF18B).	[11]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinesin-like protein KIF18B (KIF18B).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Kinesin-like protein KIF18B (KIF18B).	[19]

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 decreases the methylation of Kinesin-like protein KIF18B (KIF18B).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Kinesin-like protein KIF18B (KIF18B).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Kinesin-like protein KIF18B (KIF18B).	[16]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Bioinformatics Analysis Suggests the Combined Expression of AURKB and KIF18B Being an Important Event in the Development of Clear Cell Renal Cell Carcinoma.Pathol Oncol Res. 2020 Jul;26(3):1583-1594. doi: 10.1007/s12253-019-00740-y. Epub 2019 Sep 5.
• [3] Kinesin family member 18B: A contributor and facilitator in the proliferation and metastasis of cutaneous melanoma.J Biochem Mol Toxicol. 2019 Dec;33(12):e22409. doi: 10.1002/jbt.22409. Epub 2019 Oct 16.
• [4] Translating bioinformatics in oncology: guilt-by-profiling analysis and identification of KIF18B and CDCA3 as novel driver genes in carcinogenesis.Bioinformatics. 2015 Jan 15;31(2):216-24. doi: 10.1093/bioinformatics/btu586. Epub 2014 Sep 18.
• [5] KIF18B as a regulator in microtubule movement accelerates tumor progression and triggers poor outcome in lung adenocarcinoma.Tissue Cell. 2019 Dec;61:44-50. doi: 10.1016/j.tice.2019.09.001. Epub 2019 Sep 3.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] 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.