Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWZSX5C)

• DOT Name: Kelch-like protein 24 (KLHL24)
• Synonyms: Kainate receptor-interacting protein for GluR6; KRIP6; Protein DRE1
• Gene Name: KLHL24
• Related Disease:
  Arrhythmia
  Cardiomyopathy
  Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies
  Epidermolysis bullosa
  Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
  Hypertrophic cardiomyopathy
  Dilated cardiomyopathy
  Epidermolysis bullosa simplex
• UniProt ID: KLH24_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MVLILGRRLNREDLGVRDSPATKRKVFEMDPKSLTGHEFFDFSSGSSHAENILQIFNEFR
  DSRLFTDVIICVEGKEFPCHRAVLSACSSYFRAMFCNDHRESREMLVEINGILAEAMECF
  LQYVYTGKVKITTENVQYLFETSSLFQISVLRDACAKFLEEQLDPCNCLGIQRFADTHSL
  KTLFTKCKNFALQTFEDVSQHEEFLELDKDELIDYICSDELVIGKEEMVFEAVMRWVYRA
  VDLRRPLLHELLTHVRLPLLHPNYFVQTVEVDQLIQNSPECYQLLHEARRYHILGNEMMS
  PRTRPRRSTGYSEVIVVVGGCERVGGFNLPYTECYDPVTGEWKSLAKLPEFTKSEYAVCA
  LRNDILVSGGRINSRDVWIYNSQLNIWIRVASLNKGRWRHKMAVLLGKVYVVGGYDGQNR
  LSSVECYDSFSNRWTEVAPLKEAVSSPAVTSCVGKLFVIGGGPDDNTCSDKVQSYDPETN
  SWLLRAAIPIAKRCITAVSLNNLIYVAGGLTKAIYCYDPVEDYWMHVQNTFSRQENCGMS
  VCNGKIYILGGRRENGEATDTILCYDPATSIITGVAAMPRPVSYHGCVTIHRYNEKCFKL
• Function: Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity. As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation. Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties. Has a crucial role in cardiac development and function.
• Tissue Specificity: Expressed in the skin . Found in keratinocytes, dermal fibroblasts, and melanocytes . Basal-layer keratinocytes have lower KLHL24 expression than suprabasal keratinocytes . Expressed in the brain, spinal cord, liver, testis, heart and at higher levels in the skeletal muscle .

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmia	DISFF2NI	Strong	Altered Expression	[1]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[1]
Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies	DISEGA0S	Strong	Autosomal recessive	[1]
Epidermolysis bullosa	DISVOTZQ	Strong	Genetic Variation	[2]
Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss	DIS0SWCR	Strong	Autosomal dominant	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Moderate	Autosomal recessive	[4]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[5]
Epidermolysis bullosa simplex	DIS2CZ6X	Limited	Genetic Variation	[5]

40 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 24 (KLHL24).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kelch-like protein 24 (KLHL24).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kelch-like protein 24 (KLHL24).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 24 (KLHL24).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kelch-like protein 24 (KLHL24).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Kelch-like protein 24 (KLHL24).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kelch-like protein 24 (KLHL24).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Kelch-like protein 24 (KLHL24).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kelch-like protein 24 (KLHL24).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kelch-like protein 24 (KLHL24).	[16]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Kelch-like protein 24 (KLHL24).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kelch-like protein 24 (KLHL24).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Kelch-like protein 24 (KLHL24).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Kelch-like protein 24 (KLHL24).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Kelch-like protein 24 (KLHL24).	[20]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Kelch-like protein 24 (KLHL24).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Kelch-like protein 24 (KLHL24).	[22]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Kelch-like protein 24 (KLHL24).	[23]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Kelch-like protein 24 (KLHL24).	[24]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Kelch-like protein 24 (KLHL24).	[24]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Kelch-like protein 24 (KLHL24).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kelch-like protein 24 (KLHL24).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kelch-like protein 24 (KLHL24).	[16]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Kelch-like protein 24 (KLHL24).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Kelch-like protein 24 (KLHL24).	[27]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Kelch-like protein 24 (KLHL24).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Kelch-like protein 24 (KLHL24).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Kelch-like protein 24 (KLHL24).	[30]
GSK618334	DMJPXZ4	Phase 1	GSK618334 increases the expression of Kelch-like protein 24 (KLHL24).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Kelch-like protein 24 (KLHL24).	[32]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Kelch-like protein 24 (KLHL24).	[33]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Kelch-like protein 24 (KLHL24).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Kelch-like protein 24 (KLHL24).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch-like protein 24 (KLHL24).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kelch-like protein 24 (KLHL24).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Kelch-like protein 24 (KLHL24).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Kelch-like protein 24 (KLHL24).	[38]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Kelch-like protein 24 (KLHL24).	[39]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Kelch-like protein 24 (KLHL24).	[40]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Kelch-like protein 24 (KLHL24).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Kelch-like protein 24 (KLHL24).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Kelch-like protein 24 (KLHL24).	[31]

References

• [1] Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Hum Mol Genet. 2019 Jun 1;28(11):1919-1929. doi: 10.1093/hmg/ddz032.
• [2] Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet. 2016 Dec;48(12):1508-1516. doi: 10.1038/ng.3701. Epub 2016 Oct 31.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [5] KLHL24: Beyond Skin Fragility.J Invest Dermatol. 2019 Jan;139(1):22-24. doi: 10.1016/j.jid.2018.08.010.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] 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.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] 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.
• [16] 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.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] 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.
• [21] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [24] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [27] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [28] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [29] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [30] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [35] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [36] 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.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [38] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [39] Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation. Arch Toxicol. 2022 Jan;96(1):259-285. doi: 10.1007/s00204-021-03160-7. Epub 2021 Oct 13.
• [40] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.