Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNQDS00)

• DOT Name: Kinesin-like protein KIFC1 (KIFC1)
• Synonyms: Kinesin-like protein 2; Kinesin-related protein HSET
• Gene Name: KIFC1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Anaplastic astrocytoma
  Breast neoplasm
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Nervous system disease
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Primary ciliary dyskinesia
  Prostate cancer
  Prostate carcinoma
  Seminoma
  Triple negative breast cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Gastric cancer
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Meningioma
• UniProt ID: KIFC1_HUMAN
• PDB ID: 5WDH
• Pfam ID: PF00225
• Sequence:
  MDPQRSPLLEVKGNIELKRPLIKAPSQLPLSGSRLKRRPDQMEDGLEPEKKRTRGLGATT
  KITTSHPRVPSLTTVPQTQGQTTAQKVSKKTGPRCSTAIATGLKNQKPVPAVPVQKSGTS
  GVPPMAGGKKPSKRPAWDLKGQLCDLNAELKRCRERTQTLDQENQQLQDQLRDAQQQVKA
  LGTERTTLEGHLAKVQAQAEQGQQELKNLRACVLELEERLSTQEGLVQELQKKQVELQEE
  RRGLMSQLEEKERRLQTSEAALSSSQAEVASLRQETVAQAALLTEREERLHGLEMERRRL
  HNQLQELKGNIRVFCRVRPVLPGEPTPPPGLLLFPSGPGGPSDPPTRLSLSRSDERRGTL
  SGAPAPPTRHDFSFDRVFPPGSGQDEVFEEIAMLVQSALDGYPVCIFAYGQTGSGKTFTM
  EGGPGGDPQLEGLIPRALRHLFSVAQELSGQGWTYSFVASYVEIYNETVRDLLATGTRKG
  QGGECEIRRAGPGSEELTVTNARYVPVSCEKEVDALLHLARQNRAVARTAQNERSSRSHS
  VFQLQISGEHSSRGLQCGAPLSLVDLAGSERLDPGLALGPGERERLRETQAINSSLSTLG
  LVIMALSNKESHVPYRNSKLTYLLQNSLGGSAKMLMFVNISPLEENVSESLNSLRFASKV
  NQCVIGTAQANRK
• Function: Minus end-directed microtubule-dependent motor required for bipolar spindle formation. May contribute to movement of early endocytic vesicles. Regulates cilium formation and structure.
• 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

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Primary ciliary dyskinesia	DISOBC7V	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Seminoma	DIS3J8LJ	Strong	Biomarker	[11]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
Bladder cancer	DISUHNM0	moderate	Biomarker	[13]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[2]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[14]
Gastric cancer	DISXGOUK	moderate	Biomarker	[15]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[14]
Stomach cancer	DISKIJSX	moderate	Biomarker	[15]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[13]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[13]
Meningioma	DISPT4TG	Limited	Biomarker	[16]

3 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-like protein KIFC1 (KIFC1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kinesin-like protein KIFC1 (KIFC1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kinesin-like protein KIFC1 (KIFC1).	[45]

27 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 KIFC1 (KIFC1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinesin-like protein KIFC1 (KIFC1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Kinesin-like protein KIFC1 (KIFC1).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kinesin-like protein KIFC1 (KIFC1).	[27]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[28]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[28]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Kinesin-like protein KIFC1 (KIFC1).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[30]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[31]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[32]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[33]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[34]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[35]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[36]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[37]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Kinesin-like protein KIFC1 (KIFC1).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[41]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[43]
PJ34	DMXO6YH	Preclinical	PJ34 decreases the expression of Kinesin-like protein KIFC1 (KIFC1).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinesin-like protein KIFC1 (KIFC1).	[23]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Kinesin-like protein KIFC1 (KIFC1).	[39]

References

• [1] A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas.J Ovarian Res. 2016 Mar 18;9:17. doi: 10.1186/s13048-016-0224-0.
• [2] Prognostic and clinicopathological significance of kinesin family member C1 in various cancers: A meta-analysis.Medicine (Baltimore). 2019 Oct;98(40):e17346. doi: 10.1097/MD.0000000000017346.
• [3] Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma.Brain Res. 2010 Sep 17;1352:200-7. doi: 10.1016/j.brainres.2010.06.060. Epub 2010 Jun 30.
• [4] Effects of TPX2 gene on radiotherapy sensitization in breast cancer stem cells.Oncol Lett. 2017 Aug;14(2):1531-1535. doi: 10.3892/ol.2017.6277. Epub 2017 May 29.
• [5] MiR-29a-5p inhibits proliferation and invasion and induces apoptosis in endometrial carcinoma via targeting TPX2.Cell Cycle. 2018;17(10):1268-1278. doi: 10.1080/15384101.2018.1475829. Epub 2018 Jul 23.
• [6] KIFC1 regulated by miR-532-3p promotes epithelial-to-mesenchymal transition and metastasis of hepatocellular carcinoma via gankyrin/AKT signaling.Oncogene. 2019 Jan;38(3):406-420. doi: 10.1038/s41388-018-0440-8. Epub 2018 Aug 16.
• [7] KIFCI, a novel putative prognostic biomarker for ovarian adenocarcinomas: delineating protein interaction networks and signaling circuitries.J Ovarian Res. 2014 May 12;7:53. doi: 10.1186/1757-2215-7-53. eCollection 2014.
• [8] Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon.J Neurosci. 2019 May 15;39(20):3792-3811. doi: 10.1523/JNEUROSCI.3099-18.2019. Epub 2019 Feb 25.
• [9] Genomic organization of the HSET locus and the possible association of HLA-linked genes with immotile cilia syndrome (ICS).Immunogenetics. 1999 Jul;49(7-8):644-52. doi: 10.1007/s002510050660.
• [10] KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer.J Clin Med. 2019 Feb 9;8(2):225. doi: 10.3390/jcm8020225.
• [11] C-terminal kinesin motor KIFC1 participates in facilitating proper cell division of human seminoma.Oncotarget. 2017 May 24;8(37):61373-61384. doi: 10.18632/oncotarget.18139. eCollection 2017 Sep 22.
• [12] Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer.Sci Rep. 2017 Feb 20;7:42289. doi: 10.1038/srep42289.
• [13] Kinesin family member C1 accelerates bladder cancer cell proliferation and induces epithelial-mesenchymal transition via Akt/GSK3 signaling.Cancer Sci. 2019 Sep;110(9):2822-2833. doi: 10.1111/cas.14126. Epub 2019 Jul 23.
• [14] Kinesin Motor Protein KIFC1 Is a Target Protein of miR-338-3p and Is Associated With Poor Prognosis and Progression of Renal Cell Carcinoma.Oncol Res. 2018 Dec 27;27(1):125-137. doi: 10.3727/096504018X15213115046567. Epub 2018 Mar 21.
• [15] Overexpression of KIFC1 and its association with spheroid formation in esophageal squamous cell carcinoma.Pathol Res Pract. 2017 Nov;213(11):1388-1393. doi: 10.1016/j.prp.2017.09.009. Epub 2017 Sep 12.
• [16] Identification of KIF11 As a Novel Target in Meningioma.Cancers (Basel). 2019 Apr 15;11(4):545. doi: 10.3390/cancers11040545.
• [17] 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.
• [18] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [19] 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.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [28] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [29] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [30] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [31] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [32] 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.
• [33] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [34] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [35] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [36] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [37] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [38] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [39] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [40] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [41] 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.
• [42] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [43] 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.
• [44] KIFC1 is a novel potential therapeutic target for breast cancer. Cancer Biol Ther. 2015;16(9):1316-22. doi: 10.1080/15384047.2015.1070980. Epub 2015 Jul 15.
• [45] 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.