Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYA7UXS)

• DOT Name: Small kinetochore-associated protein (KNSTRN)
• Synonyms: SKAP; Kinetochore-localized astrin-binding protein; Kinastrin; Kinetochore-localized astrin/SPAG5-binding protein; TRAF4-associated factor 1
• Gene Name: KNSTRN
• Related Disease:
  Apparent mineralocorticoid excess
  Chronic renal failure
  Cutaneous melanoma
  Cutaneous squamous cell carcinoma
  End-stage renal disease
  Endometrial cancer
  Endometrial carcinoma
  High blood pressure
  Squamous cell carcinoma
  Advanced cancer
  Actinic keratosis
  Type-1/2 diabetes
• UniProt ID: SKAP_HUMAN
• Sequence:
  MAAPEAPPLDRVFRTTWLSTECDSHPLPPSYRKFLFETQAADLAGGTTVAAGNLLNESEK
  DCGQDRRAPGVQPCRLVTMTSVVKTVYSLQPPSALSGGQPADTQTRATSKSLLPVRSKEV
  DVSKQLHSGGPENDVTKITKLRRENGQMKATDTATRRNVRKGYKPLSKQKSEEELKDKNQ
  LLEAVNKQLHQKLTETQGELKDLTQKVELLEKFRDNCLAILESKGLDPALGSETLASRQE
  STTDHMDSMLLLETLQEELKLFNETAKKQMEELQALKVKLEMKEERVRFLEQQTLCNNQV
  NDLTTALKEMEQLLEM
• Function: Essential component of the mitotic spindle required for faithful chromosome segregation and progression into anaphase. Promotes the metaphase-to-anaphase transition and is required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture. The astrin (SPAG5)-kinastrin (SKAP) complex promotes stable microtubule-kinetochore attachments. Required for kinetochore oscillations and dynamics of microtubule plus-ends during live cell mitosis, possibly by forming a link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division. May be involved in UV-induced apoptosis via its interaction with PRPF19; however, these results need additional evidences.
• Tissue Specificity: Widely expressed, including in skin.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Apparent mineralocorticoid excess	DISRJBUV	Strong	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[1]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[2]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Genetic Variation	[3]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[5]
Actinic keratosis	DISR1RC5	Limited	Genetic Variation	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Small kinetochore-associated protein (KNSTRN).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small kinetochore-associated protein (KNSTRN).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Small kinetochore-associated protein (KNSTRN).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small kinetochore-associated protein (KNSTRN).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Small kinetochore-associated protein (KNSTRN).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Small kinetochore-associated protein (KNSTRN).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small kinetochore-associated protein (KNSTRN).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Small kinetochore-associated protein (KNSTRN).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Small kinetochore-associated protein (KNSTRN).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Small kinetochore-associated protein (KNSTRN).	[15]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Small kinetochore-associated protein (KNSTRN).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Small kinetochore-associated protein (KNSTRN).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Small kinetochore-associated protein (KNSTRN).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small kinetochore-associated protein (KNSTRN).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Small kinetochore-associated protein (KNSTRN).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Small kinetochore-associated protein (KNSTRN).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Small kinetochore-associated protein (KNSTRN).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Small kinetochore-associated protein (KNSTRN).	[24]

2 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 affects the methylation of Small kinetochore-associated protein (KNSTRN).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Small kinetochore-associated protein (KNSTRN).	[23]

References

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• [2] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [3] Somatic mutations in kinetochore gene KNSTRN are associated with basal proliferating actinic keratoses and cutaneous squamous cell carcinoma.J Eur Acad Dermatol Venereol. 2019 Aug;33(8):1535-1540. doi: 10.1111/jdv.15615. Epub 2019 May 8.
• [4] Clinical and Expression Significance of AKT1 by Co-expression Network Analysis in Endometrial Cancer.Front Oncol. 2019 Nov 6;9:1147. doi: 10.3389/fonc.2019.01147. eCollection 2019.
• [5] Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma.Nat Genet. 2014 Oct;46(10):1060-2. doi: 10.1038/ng.3091. Epub 2014 Sep 7.
• [6] Adverse maternal exposures, methylation of glucocorticoid-related genes and perinatal outcomes: a systematic review.Epigenomics. 2016 Jul;8(7):925-44. doi: 10.2217/epi.16.9. Epub 2016 Jul 6.
• [7] 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.
• [8] 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.
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• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] 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.
• [24] 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.