Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1J6NAW)

• DOT Name: Kinesin-like protein KIF7 (KIF7)
• Gene Name: KIF7
• Related Disease:
  Acrocallosal syndrome
  Hereditary hemochromatosis
  Retinitis pigmentosa 2
  Bardet-Biedl syndrome 1
  Choriocarcinoma
  Ciliopathy
  Cleft palate
  Epithelial ovarian cancer
  Germ cell tumor
  Gestational trophoblastic neoplasia
  Hydrolethalus syndrome 2
  Intellectual disability
  Isolated cleft palate
  Melanoma
  Muscular dystrophy
  Neoplasm
  Polydactyly
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Megalencephaly
  Multiple epiphyseal dysplasia
  Hydrolethalus syndrome
  Multiple epiphyseal dysplasia, Al-Gazali type
  Orofaciodigital syndrome type 6
  Joubert syndrome
• UniProt ID: KIF7_HUMAN
• PDB ID: 2XT3; 4A14; 6MLQ; 6MLR; 7RX0
• Pfam ID: PF00225
• Sequence:
  MGLEAQRLPGAEEAPVRVALRVRPLLPKELLHGHQSCLQVEPGLGRVTLGRDRHFGFHVV
  LAEDAGQEAVYQACVQPLLEAFFEGFNATVFAYGQTGSGKTYTMGEASVASLLEDEQGIV
  PRAMAEAFKLIDENDLLDCLVHVSYLEVYKEEFRDLLEVGTASRDIQLREDERGNVVLCG
  VKEVDVEGLDEVLSLLEMGNAARHTGATHLNHLSSRSHTVFTVTLEQRGRAPSRLPRPAP
  GQLLVSKFHFVDLAGSERVLKTGSTGERLKESIQINSSLLALGNVISALGDPQRRGSHIP
  YRDSKITRILKDSLGGNAKTVMIACVSPSSSDFDETLNTLNYASRAQNIRNRATVNWRPE
  AERPPEETASGARGPPRHRSETRIIHRGRRAPGPATASAAAAMRLGAECARYRACTDAAY
  SLLRELQAEPGLPGAAARKVRDWLCAVEGERSALSSASGPDSGIESASVEDQAAQGAGGR
  KEDEGAQQLLTLQNQVARLEEENRDFLAALEDAMEQYKLQSDRLREQQEEMVELRLRLEL
  VRPGWGGPRLLNGLPPGSFVPRPHTAPLGGAHAHVLGMVPPACLPGDEVGSEQRGEQVTN
  GREAGAELLTEVNRLGSGSSAASEEEEEEEEPPRRTLHLRRNRISNCSQRAGARPGSLPE
  RKGPELCLEELDAAIPGSRAVGGSKARVQARQVPPATASEWRLAQAQQKIRELAINIRMK
  EELIGELVRTGKAAQALNRQHSQRIRELEQEAEQVRAELSEGQRQLRELEGKELQDAGER
  SRLQEFRRRVAAAQSQVQVLKEKKQATERLVSLSAQSEKRLQELERNVQLMRQQQGQLQR
  RLREETEQKRRLEAEMSKRQHRVKELELKHEQQQKILKIKTEEIAAFQRKRRSGSNGSVV
  SLEQQQKIEEQKKWLDQEMEKVLQQRRALEELGEELHKREAILAKKEALMQEKTGLESKR
  LRSSQALNEDIVRVSSRLEHLEKELSEKSGQLRQGSAQSQQQIRGEIDSLRQEKDSLLKQ
  RLEIDGKLRQGSLLSPEEERTLFQLDEAIEALDAAIEYKNEAITCRQRVLRASASLLSQC
  EMNLMAKLSYLSSSETRALLCKYFDKVVTLREEQHQQQIAFSELEMQLEEQQRLVYWLEV
  ALERQRLEMDRQLTLQQKEHEQNMQLLLQQSRDHLGEGLADSRRQYEARIQALEKELGRY
  MWINQELKQKLGGVNAVGHSRGGEKRSLCSEGRQAPGNEDELHLAPELLWLSPLTEGAPR
  TREETRDLVHAPLPLTWKRSSLCGEEQGSPEELRQREAAEPLVGRVLPVGEAGLPWNFGP
  LSKPRRELRRASPGMIDVRKNPL
• Function: Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms. Involved in the regulation of microtubular dynamics. Required for proper organization of the ciliary tip and control of ciliary localization of SUFU-GLI2 complexes. Required for localization of GLI3 to cilia in response to Shh. Negatively regulates Shh signaling by preventing inappropriate activation of the transcriptional activator GLI2 in the absence of ligand. Positively regulates Shh signaling by preventing the processing of the transcription factor GLI3 into its repressor form. In keratinocytes, promotes the dissociation of SUFU-GLI2 complexes, GLI2 nuclear translocation and Shh signaling activation. Involved in the regulation of epidermal differentiation and chondrocyte development.
• Tissue Specificity: Embryonic stem cells, melanotic melanoma and Jurkat T-cells. Expressed in heart, lung, liver, kidney, testis, retina, placenta, pancreas, colon, small intestin, prostate and thymus.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Motor proteins (hsa04814)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Hedgehog 'on' state (R-HSA-5632684)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrocallosal syndrome	DISKMCG2	Definitive	Autosomal recessive	[1]
Hereditary hemochromatosis	DISVG5MT	Definitive	Biomarker	[2]
Retinitis pigmentosa 2	DISLBNCM	Definitive	Altered Expression	[2]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Genetic Variation	[3]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[4]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Germ cell tumor	DIS62070	Strong	Altered Expression	[7]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Biomarker	[4]
Hydrolethalus syndrome 2	DISFADNP	Strong	Autosomal recessive	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Polydactyly	DIS25BMZ	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[10]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[11]
Multiple epiphyseal dysplasia	DIS5FZLR	moderate	Genetic Variation	[11]
Hydrolethalus syndrome	DISX56R3	Supportive	Autosomal recessive	[3]
Multiple epiphyseal dysplasia, Al-Gazali type	DISCLVHK	Supportive	Autosomal recessive	[11]
Orofaciodigital syndrome type 6	DISQY7K4	Supportive	Autosomal recessive	[12]
Joubert syndrome	DIS7P5CO	Limited	Biomarker	[13]

5 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 KIF7 (KIF7).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kinesin-like protein KIF7 (KIF7).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Kinesin-like protein KIF7 (KIF7).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kinesin-like protein KIF7 (KIF7).	[23]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Kinesin-like protein KIF7 (KIF7).	[24]

7 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 KIF7 (KIF7).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kinesin-like protein KIF7 (KIF7).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinesin-like protein KIF7 (KIF7).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Kinesin-like protein KIF7 (KIF7).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinesin-like protein KIF7 (KIF7).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinesin-like protein KIF7 (KIF7).	[20]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Kinesin-like protein KIF7 (KIF7).	[21]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Arl3 and RP2 regulate the trafficking of ciliary tip kinesins.Hum Mol Genet. 2017 Jul 1;26(13):2480-2492. doi: 10.1093/hmg/ddx143.
• [3] KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011 Jun;43(6):601-6. doi: 10.1038/ng.826. Epub 2011 May 8.
• [4] Downregulation of the gli transcription factors regulator Kif7 facilitates cell survival and migration of choriocarcinoma cells.PLoS One. 2014 Sep 29;9(9):e108248. doi: 10.1371/journal.pone.0108248. eCollection 2014.
• [5] Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice.Hum Mol Genet. 2019 Mar 15;28(6):877-887. doi: 10.1093/hmg/ddy392.
• [6] Low expression of KIF7 indicates poor prognosis in epithelial ovarian cancer.Cancer Biomark. 2019;26(4):481-489. doi: 10.3233/CBM-190328.
• [7] Characterization of KIF7 gene in silico.Int J Oncol. 2004 Dec;25(6):1881-6.
• [8] Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13377-82. doi: 10.1073/pnas.0906944106. Epub 2009 Jul 29.
• [9] Mapping Breakpoints of Complex Chromosome Rearrangements Involving a Partial Trisomy 15q23.1-q26.2 Revealed by Next Generation Sequencing and Conventional Techniques.PLoS One. 2016 May 24;11(5):e0154574. doi: 10.1371/journal.pone.0154574. eCollection 2016.
• [10] KIF7 attenuates prostate tumor growth through LKB1-mediated AKT inhibition.Oncotarget. 2017 Apr 26;8(33):54558-54571. doi: 10.18632/oncotarget.17421. eCollection 2017 Aug 15.
• [11] A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Orphanet J Rare Dis. 2012 May 15;7:27. doi: 10.1186/1750-1172-7-27.
• [12] Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [13] Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.Eur J Hum Genet. 2018 Feb;26(2):197-209. doi: 10.1038/s41431-017-0019-9. Epub 2018 Jan 10.
• [14] 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.
• [15] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] 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.
• [19] 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.
• [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] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [22] 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.
• [23] 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.
• [24] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.