Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSMBJ24)

• DOT Name: Kinesin-like protein KIF18A (KIF18A)
• Synonyms: Marrow stromal KIF18A; MS-KIF18A
• Gene Name: KIF18A
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Estrogen-receptor positive breast cancer
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Plasma cell myeloma
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Liver cancer
  Metastatic malignant neoplasm
• UniProt ID: KI18A_HUMAN
• PDB ID: 3LRE; 5OAM; 5OCU; 5OGC; 7RSI
• Pfam ID: PF00225
• Sequence:
  MSVTEEDLCHHMKVVVRVRPENTKEKAAGFHKVVHVVDKHILVFDPKQEEVSFFHGKKTT
  NQNVIKKQNKDLKFVFDAVFDETSTQSEVFEHTTKPILRSFLNGYNCTVLAYGATGAGKT
  HTMLGSADEPGVMYLTMLHLYKCMDEIKEEKICSTAVSYLEVYNEQIRDLLVNSGPLAVR
  EDTQKGVVVHGLTLHQPKSSEEILHLLDNGNKNRTQHPTDMNATSSRSHAVFQIYLRQQD
  KTASINQNVRIAKMSLIDLAGSERASTSGAKGTRFVEGTNINRSLLALGNVINALADSKR
  KNQHIPYRNSKLTRLLKDSLGGNCQTIMIAAVSPSSVFYDDTYNTLKYANRAKDIKSSLK
  SNVLNVNNHITQYVKICNEQKAEILLLKEKLKAYEEQKAFTNENDQAKLMISNPQEKEIE
  RFQEILNCLFQNREEIRQEYLKLEMLLKENELKSFYQQQCHKQIEMMCSEDKVEKATGKR
  DHRLAMLKTRRSYLEKRREEELKQFDENTNWLHRVEKEMGLLSQNGHIPKELKKDLHCHH
  LHLQNKDLKAQIRHMMDLACLQEQQHRQTEAVLNALLPTLRKQYCTLKEAGLSNAAFESD
  FKEIEHLVERKKVVVWADQTAEQPKQNDLPGISVLMTFPQLGPVQPIPCCSSSGGTNLVK
  IPTEKRTRRKLMPSPLKGQHTLKSPPSQSVQLNDSLSKELQPIVYTPEDCRKAFQNPSTV
  TLMKPSSFTTSFQAISSNINSDNCLKMLCEVAIPHNRRKECGQEDLDSTFTICEDIKSSK
  CKLPEQESLPNDNKDILQRLDPSSFSTKHSMPVPSMVPSYMAMTTAAKRKRKLTSSTSNS
  SLTADVNSGFAKRVRQDNSSEKHLQENKPTMEHKRNICKINPSMVRKFGRNISKGNLR
• Function: Microtubule-depolymerizing kinesin which plays a role in chromosome congression by reducing the amplitude of preanaphase oscillations and slowing poleward movement during anaphase, thus suppressing chromosome movements. May stabilize the CENPE-BUB1B complex at the kinetochores during early mitosis and maintains CENPE levels at kinetochores during chromosome congression.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Kinesins (R-HSA-983189)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[8]
Liver cancer	DISDE4BI	Disputed	Altered Expression	[7]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Kinesin-like protein KIF18A (KIF18A).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Kinesin-like protein KIF18A (KIF18A).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Kinesin-like protein KIF18A (KIF18A).	[29]

23 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-like protein KIF18A (KIF18A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinesin-like protein KIF18A (KIF18A).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinesin-like protein KIF18A (KIF18A).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kinesin-like protein KIF18A (KIF18A).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[22]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[23]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinesin-like protein KIF18A (KIF18A).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Kinesin-like protein KIF18A (KIF18A).	[32]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Kinesin-like protein KIF18A (KIF18A).	[33]

References

• [1] Kinesin family member-18A (KIF18A) is a predictive biomarker of poor benefit from endocrine therapy in early ER+breast cancer.Breast Cancer Res Treat. 2019 Jan;173(1):93-102. doi: 10.1007/s10549-018-4978-5. Epub 2018 Oct 10.
• [2] Identification of significant gene and pathways involved in HBV-related hepatocellular carcinoma by bioinformatics analysis.PeerJ. 2019 Jul 30;7:e7408. doi: 10.7717/peerj.7408. eCollection 2019.
• [3] Overexpression of KIF18A promotes cell proliferation, inhibits apoptosis, and independently predicts unfavorable prognosis in lung adenocarcinoma.IUBMB Life. 2019 Jul;71(7):942-955. doi: 10.1002/iub.2030. Epub 2019 Feb 28.
• [4] High kinesin family member 18A expression correlates with poor prognosis in primary lung adenocarcinoma.Thorac Cancer. 2019 May;10(5):1103-1110. doi: 10.1111/1759-7714.13051. Epub 2019 Mar 25.
• [5] Expression of KIF18A Is Associated with Increased Tumor Stage and Cell Proliferation in Prostate Cancer.Med Sci Monit. 2019 Aug 27;25:6418-6428. doi: 10.12659/MSM.917352.
• [6] Search for rare protein altering variants influencing susceptibility to multiple myeloma.Oncotarget. 2017 May 30;8(22):36203-36210. doi: 10.18632/oncotarget.15874.
• [7] The role of kinesin KIF18A in the invasion and metastasis of hepatocellular carcinoma.World J Surg Oncol. 2018 Feb 21;16(1):36. doi: 10.1186/s12957-018-1342-5.
• [8] Kinesin 18A expression: clinical relevance to colorectal cancer progression.Int J Cancer. 2011 Dec 1;129(11):2543-52. doi: 10.1002/ijc.25916. Epub 2011 Jun 9.
• [9] Kinesin Family Member 18A (KIF18A) Contributes to the Proliferation, Migration, and Invasion of Lung Adenocarcinoma Cells In Vitro and In Vivo.Dis Markers. 2019 Oct 22;2019:6383685. doi: 10.1155/2019/6383685. eCollection 2019.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] 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.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [23] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [24] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [25] 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.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [33] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.