Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK6WARI)

• DOT Name: Kelch-like protein 42 (KLHL42)
• Synonyms: Cullin-3-binding protein 9; Ctb9; Kelch domain-containing protein 5
• Gene Name: KLHL42
• Related Disease:
  Non-insulin dependent diabetes
  Sezary syndrome
  Osteoarthritis
• UniProt ID: KLH42_HUMAN
• Pfam ID: PF07707 ; PF01344
• Sequence:
  MSAEEMVQIRLEDRCYPVSKRKLIEQSDYFRALYRSGMREALSQEAGGPEVQQLRGLSAP
  GLRLVLDFINAGGAREGWLLGPRGEKGGGVDEDEEMDEVSLLSELVEAASFLQVTSLLQL
  LLSQVRLNNCLEMYRLAQVYGLPDLQEACLRFMVVHFHEVLCKPQFHLLGSPPQAPGDVS
  LKQRLREARMTGTPVLVALGDFLGGPLAPHPYQGEPPSMLRYEEMTERWFPLANNLPPDL
  VNVRGYGSAILDNYLFIVGGYRITSQEISAAHSYNPSTNEWLQVASMNQKRSNFKLVAVN
  SKLYAIGGQAVSNVECYNPEQDAWNFVAPLPNPLAEFSACECKGKIYVIGGYTTRDRNMN
  ILQYCPSSDMWTLFETCDVHIRKQQMVSVEETIYIVGGCLHELGPNRRSSQSEDMLTVQS
  YNTVTRQWLYLKENTSKSGLNLTCALHNDGIYIMSRDVTLSTSLEHRVFLKYNIFSDSWE
  AFRRFPAFGHNLLVSSLYLPNKAET
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL42) E3 ubiquitin ligase complex mediates the ubiquitination and subsequent degradation of KATNA1. Involved in microtubule dynamics throughout mitosis.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]
Sezary syndrome	DISFMTC7	Strong	Altered Expression	[2]
Osteoarthritis	DIS05URM	moderate	Genetic Variation	[3]

15 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 42 (KLHL42).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kelch-like protein 42 (KLHL42).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 42 (KLHL42).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kelch-like protein 42 (KLHL42).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kelch-like protein 42 (KLHL42).	[8]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Kelch-like protein 42 (KLHL42).	[9]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose increases the expression of Kelch-like protein 42 (KLHL42).	[10]
Bleomycin	DMNER5S	Approved	Bleomycin increases the expression of Kelch-like protein 42 (KLHL42).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kelch-like protein 42 (KLHL42).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kelch-like protein 42 (KLHL42).	[8]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Kelch-like protein 42 (KLHL42).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Kelch-like protein 42 (KLHL42).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kelch-like protein 42 (KLHL42).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch-like protein 42 (KLHL42).	[14]
DZNep	DM0JXBK	Investigative	DZNep increases the expression of Kelch-like protein 42 (KLHL42).	[10]

References

• [1] Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.PLoS One. 2015 May 7;10(5):e0126363. doi: 10.1371/journal.pone.0126363. eCollection 2015.
• [2] Szary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3.Leukemia. 2008 Feb;22(2):393-9. doi: 10.1038/sj.leu.2405044. Epub 2007 Nov 22.
• [3] Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X-Ray Absorptiometry-Derived Hip Shape in a Population-Based Cohort of PerimenopausalWomen.Arthritis Rheumatol. 2018 Dec;70(12):1984-1993. doi: 10.1002/art.40584. Epub 2018 Oct 27.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [10] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [14] 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.