Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5VCKSM)

• DOT Name: Centrosomal protein kizuna (KIZ)
• Synonyms: Polo-like kinase 1 substrate 1
• Gene Name: KIZ
• Related Disease:
  Inherited retinal dystrophy
  Retinitis pigmentosa 69
  Retinitis pigmentosa
  Blindness
• UniProt ID: KIZ_HUMAN
• Sequence:
  MSRTLASAVPLSSPDYYERLGQLQHGLRDSEKKRLDLEKKLYEYNQSDTCRVKLKYVKLK
  NYLKEICESEKKAHTRNQEYLKRFERVQAHVVHFTTNTEKLQKLKLEYETQIKKMLCSKD
  SLGLKEELTDEDREKVAVHEGINSGTAMSRGLYQPATIFMGRQMSAILSMRDFSTEHKSP
  QPTKNFSIPDPHSHRQTAQSSNVTDSCVVQTSNDTQCLNKSDNIDGKASLQIGEKMPVTA
  SVLSEEEQTHCLEIGSNTRHGKSNLSEGKKSAELNSPLRERLSPENRTTDLKCDSSSGSE
  GEILTREHIEVEEKRASPPVSPIPVSEYCESENKWSQEKHSPWEGVSDHLAHREPKSQKP
  FRKMQEEEEESWSTSSDLTISISEDDLILESPEPQPNPGGKMEGEDGIEALKLIHAEQER
  VALSTEKNCILQTLSSPDSEKESSTNAPTREPGQTPDSDVPRAQVGQHVATLKEHDNSVK
  EEATALLRKALTEECGRRSAIHSSESSCSLPSILNDNSGIKEAKPAVWLNSVPTREQEVS
  SGCGDKSKKENVAADIPITETEAYQLLKKATLQDNTNQTENRFQKTDASVSHLSGLNIGS
  GAFETKTANKIASEASFSSSEGSPLSRHENKKKPVINLKSNALWDESDDSNSEIEAALRP
  RNHNTDDSDDFYD
• Function: Centrosomal protein required for establishing a robust mitotic centrosome architecture that can endure the forces that converge on the centrosomes during spindle formation. Required for stabilizing the expanded pericentriolar material around the centriole.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 69	DIS264FU	Strong	Autosomal recessive	[2]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[3]
Blindness	DISTIM10	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Centrosomal protein kizuna (KIZ).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein kizuna (KIZ).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centrosomal protein kizuna (KIZ).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centrosomal protein kizuna (KIZ).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Centrosomal protein kizuna (KIZ).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Centrosomal protein kizuna (KIZ).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Centrosomal protein kizuna (KIZ).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Centrosomal protein kizuna (KIZ).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Centrosomal protein kizuna (KIZ).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Centrosomal protein kizuna (KIZ).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Centrosomal protein kizuna (KIZ).	[15]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Centrosomal protein kizuna (KIZ).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Centrosomal protein kizuna (KIZ).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Centrosomal protein kizuna (KIZ).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Centrosomal protein kizuna (KIZ).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Centrosomal protein kizuna (KIZ).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Centrosomal protein kizuna (KIZ).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Centrosomal protein kizuna (KIZ).	[18]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Expression and functional analysis of Gm114, a putative mammalian ortholog of Drosophila bam. Dev Biol. 2008 Jun 1;318(1):73-81. doi: 10.1016/j.ydbio.2008.03.001. Epub 2008 Mar 14.
• [3] Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. Am J Hum Genet. 2014 Apr 3;94(4):625-33. doi: 10.1016/j.ajhg.2014.03.005. Epub 2014 Mar 27.
• [4] Retinal dystrophy associated with a Kizuna (KIZ) mutation and a predominantly macular phenotype.Ophthalmic Genet. 2019 Oct;40(5):455-460. doi: 10.1080/13816810.2019.1666880. Epub 2019 Sep 26.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [13] 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.
• [14] 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.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [17] 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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.