Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4Q3LHV)

• DOT Name: Kinetochore scaffold 1 (KNL1)
• Synonyms: ALL1-fused gene from chromosome 15q14 protein; AF15q14; Bub-linking kinetochore protein; Blinkin; Cancer susceptibility candidate gene 5 protein; Cancer/testis antigen 29; CT29; Kinetochore-null protein 1; Protein CASC5; Protein D40/AF15q14
• Gene Name: KNL1
• Related Disease:
  Acute lymphocytic leukaemia
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Familial prostate carcinoma
  Isolated congenital microcephaly
  Lung cancer
  Lung neoplasm
  Melanoma
  Microcephaly 4, primary, autosomal recessive
  Neoplasm
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Sarcoidosis
  leukaemia
  Leukemia
  Autosomal recessive primary microcephaly
  Acute myelogenous leukaemia
  Gastric cancer
  Stomach cancer
• UniProt ID: KNL1_HUMAN
• PDB ID: 3SI5; 4A1G; 4NF9; 4NFA
• Pfam ID: PF18210 ; PF19221
• Sequence:
  MDGVSSEANEENDNIERPVRRRHSSILKPPRSPLQDLRGGNERVQESNALRNKKNSRRVS
  FADTIKVFQTESHMKIVRKSEMEGCSAMVPSQLQLLPPGFKRFSCLSLPETETGENLLLI
  QNKKLEDNYCEITGMNTLLSAPIHTQMQQKEFSIIEHTRERKHANDQTVIFSDENQMDLT
  SSHTVMITKGLLDNPISEKSTKIDTTSFLANLKLHTEDSRMKKEVNFSVDQNTSSENKID
  FNDFIKRLKTGKCSAFPDVPDKENFEIPIYSKEPNSASSTHQMHVSLKEDENNSNITRLF
  REKDDGMNFTQCHTANIQTLIPTSSETNSRESKGNDITIYGNDFMDLTFNHTLQILPATG
  NFSEIENQTQNAMDVTTGYGTKASGNKTVFKSKQNTAFQDLSINSADKIHITRSHIMGAE
  THIVSQTCNQDARILAMTPESIYSNPSIQGCKTVFYSSCNDAMEMTKCLSNMREEKNLLK
  HDSNYAKMYCNPDAMSSLTEKTIYSGEENMDITKSHTVAIDNQIFKQDQSNVQIAAAPTP
  EKEMMLQNLMTTSEDGKMNVNCNSVPHVSKERIQQSLSNPLSISLTDRKTELLSGENMDL
  TESHTSNLGSQVPLAAYNLAPESTSESHSQSKSSSDECEEITKSRNEPFQRSDIIAKNSL
  TDTWNKDKDWVLKILPYLDKDSPQSADCNQEIATSHNIVYCGGVLDKQITNRNTVSWEQS
  LFSTTKPLFSSGQFSMKNHDTAISSHTVKSVLGQNSKLAEPLRKSLSNPTPDYCHDKMII
  CSEEEQNMDLTKSHTVVIGFGPSELQELGKTNLEHTTGQLTTMNRQIAVKVEKCGKSPIE
  KSGVLKSNCIMDVLEDESVQKPKFPKEKQNVKIWGRKSVGGPKIDKTIVFSEDDKNDMDI
  TKSYTIEINHRPLLEKRDCHLVPLAGTSETILYTCRQDDMEITRSHTTALECKTVSPDEI
  TTRPMDKTVVFVDNHVELEMTESHTVFIDYQEKERTDRPNFELSQRKSLGTPTVICTPTE
  ESVFFPGNGESDRLVANDSQLTPLEEWSNNRGPVEVADNMELSKSATCKNIKDVQSPGFL
  NEPLSSKSQRRKSLKLKNDKTIVFSENHKNDMDITQSCMVEIDNESALEDKEDFHLAGAS
  KTILYSCGQDDMEITRSHTTALECKTLLPNEIAIRPMDKTVLFTDNYSDLEVTDSHTVFI
  DCQATEKILEENPKFGIGKGKNLGVSFPKDNSCVQEIAEKQALAVGNKIVLHTEQKQQLF
  AATNRTTNEIIKFHSAAMDEKVIGKVVDQACTLEKAQVESCQLNNRDRRNVDFTSSHATA
  VCGSSDNYSCLPNVISCTDNLEGSAMLLCDKDEEKANYCPVQNDLAYANDFASEYYLESE
  GQPLSAPCPLLEKEEVIQTSTKGQLDCVITLHKDQDLIKDPRNLLANQTLVYSQDLGEMT
  KLNSKRVSFKLPKDQMKVYVDDIYVIPQPHFSTDQPPLPKKGQSSINKEEVILSKAGNKS
  LNIIENSSAPICENKPKILNSEEWFAAACKKELKENIQTTNYNTALDFHSNSDVTKQVIQ
  THVNAGEAPDPVITSNVPCFHSIKPNLNNLNGKTGEFLAFQTVHLPPLPEQLLELGNKAH
  NDMHIVQATEIHNINIISSNAKDSRDEENKKSHNGAETTSLPPKTVFKDKVRRCSLGIFL
  PRLPNKRNCSVTGIDDLEQIPADTTDINHLETQPVSSKDSGIGSVAGKLNLSPSQYINEE
  NLPVYPDEINSSDSINIETEEKALIETYQKEISPYENKMGKTCNSQKRTWVQEEEDIHKE
  KKIRKNEIKFSDTTQDREIFDHHTEEDIDKSANSVLIKNLSRTPSSCSSSLDSIKADGTS
  LDFSTYRSSQMESQFLRDTICEESLREKLQDGRITIREFFILLQVHILIQKPRQSNLPGN
  FTVNTPPTPEDLMLSQYVYRPKIQIYREDCEARRQKIEELKLSASNQDKLLVDINKNLWE
  KMRHCSDKELKAFGIYLNKIKSCFTKMTKVFTHQGKVALYGKLVQSAQNEREKLQIKIDE
  MDKILKKIDNCLTEMETETKNLEDEEKNNPVEEWDSEMRAAEKELEQLKTEEEELQRNLL
  ELEVQKEQTLAQIDFMQKQRNRTEELLDQLSLSEWDVVEWSDDQAVFTFVYDTIQLTITF
  EESVVGFPFLDKRYRKIVDVNFQSLLDEDQAPPSSLLVHKLIFQYVEEKESWKKTCTTQH
  QLPKMLEEFSLVVHHCRLLGEEIEYLKRWGPNYNLMNIDINNNELRLLFSSSAAFAKFEI
  TLFLSAYYPSVPLPSTIQNHVGNTSQDDIATILSKVPLENNYLKNVVKQIYQDLFQDCHF
  YH
• Function: Performs two crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Required for attachment of the kinetochores to the spindle microtubules. Directly links BUB1 and BUB1B to kinetochores. Part of the MIS12 complex, which may be fundamental for kinetochore formation and proper chromosome segregation during mitosis. Acts in coordination with CENPK to recruit the NDC80 complex to the outer kinetochore.
• Tissue Specificity: Highly expressed in testis, where it is localized in germ cells, in particular in spermatocytes and in the pre-acrosome of round spermatids. Detected in the acrosome of ejaculated spermatozoa. Detected in adult thymus, bone marrow, colon, small intestine, appendix and placenta, and in fetal liver and thymus.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Acute myelomonocytic leukemia M4	DISRRMV2	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[1]
Microcephaly 4, primary, autosomal recessive	DIS4HVZ0	Strong	Autosomal recessive	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[4]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[8]
leukaemia	DISS7D1V	moderate	Biomarker	[9]
Leukemia	DISNAKFL	moderate	Biomarker	[9]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[10]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[11]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[12]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[12]

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 Kinetochore scaffold 1 (KNL1).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Kinetochore scaffold 1 (KNL1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Kinetochore scaffold 1 (KNL1).	[29]

22 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 Kinetochore scaffold 1 (KNL1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinetochore scaffold 1 (KNL1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinetochore scaffold 1 (KNL1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinetochore scaffold 1 (KNL1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kinetochore scaffold 1 (KNL1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinetochore scaffold 1 (KNL1).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kinetochore scaffold 1 (KNL1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinetochore scaffold 1 (KNL1).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kinetochore scaffold 1 (KNL1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinetochore scaffold 1 (KNL1).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kinetochore scaffold 1 (KNL1).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kinetochore scaffold 1 (KNL1).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Kinetochore scaffold 1 (KNL1).	[24]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Kinetochore scaffold 1 (KNL1).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinetochore scaffold 1 (KNL1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinetochore scaffold 1 (KNL1).	[28]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Kinetochore scaffold 1 (KNL1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinetochore scaffold 1 (KNL1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kinetochore scaffold 1 (KNL1).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinetochore scaffold 1 (KNL1).	[33]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Kinetochore scaffold 1 (KNL1).	[34]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Kinetochore scaffold 1 (KNL1).	[35]

References

• [1] Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14).Oncogene. 2003 Mar 6;22(9):1418-24. doi: 10.1038/sj.onc.1206272.
• [2] Targeted Knockdown of the Kinetochore Protein D40/Knl-1 Inhibits Human Cancer in a p53 Status-Independent Manner.Sci Rep. 2015 Sep 8;5:13676. doi: 10.1038/srep13676.
• [3] Effect of KNL1 on the proliferation and apoptosis of colorectal cancer cells.Technol Cancer Res Treat. 2019 Jan 1;18:1533033819858668. doi: 10.1177/1533033819858668.
• [4] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [5] Robust elimination of genome-damaged cells safeguards against brain somatic aneuploidy following Knl1 deletion.Nat Commun. 2019 Jun 13;10(1):2588. doi: 10.1038/s41467-019-10411-w.
• [6] Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers.Br J Cancer. 2002 Jun 5;86(11):1757-62. doi: 10.1038/sj.bjc.6600328.
• [7] Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet. 2012 Dec 15;21(24):5306-17. doi: 10.1093/hmg/dds386. Epub 2012 Sep 13.
• [8] Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.BMC Med Genomics. 2018 Mar 6;11(1):23. doi: 10.1186/s12920-018-0338-x.
• [9] D40/KNL1/CASC5 and autosomal recessive primary microcephaly.Congenit Anom (Kyoto). 2017 Nov;57(6):191-196. doi: 10.1111/cga.12252. Epub 2017 Nov 1.
• [10] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [11] AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).Oncogene. 2000 Sep 7;19(38):4446-50. doi: 10.1038/sj.onc.1203789.
• [12] Dysregulation of NCAPG, KNL1, miR-148a-3p, miR-193b-3p, and miR-1179 may contribute to the progression of gastric cancer.Biol Res. 2018 Nov 3;51(1):44. doi: 10.1186/s40659-018-0192-5.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [24] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [25] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [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] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [31] 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.
• [32] 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.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [34] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [35] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.