Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYOS55H)

• DOT Name: Kelch-like protein 14 (KLHL14)
• Synonyms: Protein interactor of Torsin-1A; Printor; Protein interactor of torsinA
• Gene Name: KLHL14
• Related Disease:
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Dystonia
• UniProt ID: KLH14_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MSRSGDRTSTFDPSHSDNLLHGLNLLWRKQLFCDVTLTAQGQQFHCHKAVLASCSQYFRS
  LFSSHPPLGGGVGGQDGLGAPKDQQQPPQQQPSQQQQPPPQEEPGTPSSSPDDKLLTSPR
  AINNLVLQGCSSIGLRLVLEYLYTANVTLSLDTVEEVLSVSKILHIPQVTKLCVQFLNDQ
  ISVQNYKQVCKIAALHGLEETKKLANKYLVEDVLLLNFEEMRALLDSLPPPVESELALFQ
  MSVLWLEHDRETRMQYAPDLMKRLRFALIPAPELVERVQSVDFMRTDPVCQKLLLDAMNY
  HLMPFRQHCRQSLASRIRSNKKMLLLVGGLPPGPDRLPSNLVQYYDDEKKTWKILTIMPY
  NSAHHCVVEVENFLFVLGGEDQWNPNGKHSTNFVSRYDPRFNSWIQLPPMQERRASFYAC
  RLDKHLYVIGGRNETGYLSSVECYNLETNEWRYVSSLPQPLAAHAGAVHNGKIYISGGVH
  NGEYVPWLYCYDPVMDVWARKQDMNTKRAIHTLAVMNDRLYAIGGNHLKGFSHLDVMLVE
  CYDPKGDQWNILQTPILEGRSGPGCAVLDDSIYLVGGYSWSMGAYKSSTICYCPEKGTWT
  ELEGDVAEPLAGPACVTVILPSCVPYNK

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[1]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[1]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[1]
Dystonia	DISJLFGW	Strong	Biomarker	[2]

20 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 Kelch-like protein 14 (KLHL14).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kelch-like protein 14 (KLHL14).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kelch-like protein 14 (KLHL14).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch-like protein 14 (KLHL14).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Kelch-like protein 14 (KLHL14).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kelch-like protein 14 (KLHL14).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kelch-like protein 14 (KLHL14).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Kelch-like protein 14 (KLHL14).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Kelch-like protein 14 (KLHL14).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Kelch-like protein 14 (KLHL14).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Kelch-like protein 14 (KLHL14).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch-like protein 14 (KLHL14).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kelch-like protein 14 (KLHL14).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Kelch-like protein 14 (KLHL14).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kelch-like protein 14 (KLHL14).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kelch-like protein 14 (KLHL14).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kelch-like protein 14 (KLHL14).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Kelch-like protein 14 (KLHL14).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch-like protein 14 (KLHL14).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kelch-like protein 14 (KLHL14).	[11]

1 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 decreases the phosphorylation of Kelch-like protein 14 (KLHL14).	[19]

References

• [1] A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis.Cancer Res. 2019 Nov 15;79(22):5746-5757. doi: 10.1158/0008-5472.CAN-19-0039. Epub 2019 Sep 26.
• [2] A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry.Cell Rep. 2017 Oct 17;21(3):666-678. doi: 10.1016/j.celrep.2017.09.079.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [16] 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.
• [17] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.