Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAX6SAD)

DOT Name	Kelch-like protein 1 (KLHL1)
Gene Name	KLHL1
Related Disease	Carcinoma of esophagus ( ) Esophageal cancer ( ) Neoplasm of esophagus ( ) Non-small-cell lung cancer ( ) Acute monocytic leukemia ( ) Acute myelogenous leukaemia ( ) Adenocarcinoma ( ) Bladder cancer ( ) Carcinoma ( ) Cholangiocarcinoma ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Epithelial ovarian cancer ( ) Esophageal squamous cell carcinoma ( ) Hepatitis ( ) Hepatitis C virus infection ( ) Hepatocellular carcinoma ( ) Liver cirrhosis ( ) Lung cancer ( ) Lung carcinoma ( ) Matthew-Wood syndrome ( ) Neoplasm ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pancreatic cancer ( ) Primary biliary cholangitis ( ) Renal carcinoma ( ) Renal cell carcinoma ( ) Small-cell lung cancer ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Advanced cancer ( ) B-cell lymphoma ( ) Cholestasis ( ) Congenital contractural arachnodactyly ( ) Melanoma ( ) Acute lymphocytic leukaemia ( ) Breast cancer ( ) Breast carcinoma ( ) Childhood acute lymphoblastic leukemia ( ) Dubin-Johnson syndrome ( ) Epilepsy ( ) Gallbladder carcinoma ( ) Mesothelioma ( ) Plasma cell myeloma ( ) Progressive familial intrahepatic cholestasis ( )
UniProt ID	KLHL1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF07707 ; PF00651 ; PF01344
Sequence	MSGSGRKDFDVKHILRLRWKLFSHPSPSTGGPAGGGCLQQDGSGSFEHWGPSQSRLLKSQ ERSGVSTFWKKPSSSSSSSSSPSSSSSSFNPLNGTLLPVATRLQQGAPGQGTQQPARTLF YVESLEEEVVPGMDFPGPHEKGLVLQELKVEPDNSSQATGEGCGHRLSSTGHSMTPQSDL DSSSSEEFYQAVHHAEQTFRKMESYLKQQQLCDVILIVGNRKIPAHRLVLSSVSDYFAAM FTSDVCEAKQEEIKMEGIDPNALWDLVQFAYTGCLELKEDTIENLLAAACLLQLPQVVEV CCHFLMKLLHPSNCLGIRAFADAQGCIELMKVAHSYTMENIMEVIRNQEFLLLPAEELHK LLASDDVNVPDEETIFHALMMWVKYDMQSRCNDLSMLLAFIRLPLLPPQILADLENHALF KNDLECQKLILEAMKYHLLPERRTLMQSPRTKPRKSTVGTLYAVGGMDNNKGATTIEKYD LRTNLWIQAGMMNGRRLQFGVAVIDDKLFVIGGRDGLKTLNTVECYNPKTKTWTVLPPMS THRHGLGVTVLEGPIYAVGGHDGWSYLNTVERWDPQSQQWTFVASMSIARSTVGVAALNG KLYSVGGRDGSSCLSSMEYYDPHTNKWNMCAPMCKRRGGVGVATCDGFLYAVGGHDAPAS NHCSRLLDYVERYDPKTDTWTMVAPLSMPRDAVGVCLLGDRLYAVGGYDGQTYLNTMESY DPQTNEWTQMASLNIGRAGACVVVIKQP
Function	May play a role in organizing the actin cytoskeleton of the brain cells.
Tissue Specificity	Highly expressed in brain.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Carcinoma of esophagus	DISS6G4D	Definitive	Altered Expression	[1]
Esophageal cancer	DISGB2VN	Definitive	Altered Expression	[1]
Neoplasm of esophagus	DISOLKAQ	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Hepatitis	DISXXX35	Strong	Biomarker	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Altered Expression	[15]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[15]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[17]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[10]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[18]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[19]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[8]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[20]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[21]
B-cell lymphoma	DISIH1YQ	moderate	Biomarker	[22]
Cholestasis	DISDJJWE	moderate	Biomarker	[23]
Congenital contractural arachnodactyly	DISOM1K7	moderate	Altered Expression	[24]
Melanoma	DIS1RRCY	moderate	Altered Expression	[25]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[26]
Breast cancer	DIS7DPX1	Limited	Biomarker	[27]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[27]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Altered Expression	[26]
Dubin-Johnson syndrome	DISM8TG9	Limited	Biomarker	[28]
Epilepsy	DISBB28L	Limited	Biomarker	[29]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[30]
Mesothelioma	DISKWK9M	Limited	Biomarker	[31]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[22]
Progressive familial intrahepatic cholestasis	DIS3J8HT	Limited	Biomarker	[32]
------------------------------------------------------------------------------------


⏷ Show the Full List of 47 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 1 (KLHL1).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kelch-like protein 1 (KLHL1).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kelch-like protein 1 (KLHL1).	[35]
------------------------------------------------------------------------------------

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kelch-like protein 1 (KLHL1).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Kelch-like protein 1 (KLHL1).	[36]
------------------------------------------------------------------------------------

References

1	Expression of genes related to activity of oxaliplatin and 5-fluorouracil in endoscopic biopsies of primary esophageal cancer in patients receiving oxaliplatin, 5-flourouracil and radiation: characterization and exploratory analysis with survival.J Chemother. 2006 Oct;18(5):514-24. doi: 10.1179/joc.2006.18.5.514.
2	MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer.Cancer Chemother Pharmacol. 2010 Feb;65(3):437-46. doi: 10.1007/s00280-009-1046-1. Epub 2009 Jul 1.
3	Lung resistance-related protein (LRP) predicts favorable therapeutic outcome in Acute Myeloid Leukemia.Sci Rep. 2019 Jan 23;9(1):378. doi: 10.1038/s41598-018-36780-8.
4	Chemosensitivity assessed by collagen gel droplet embedded culture drug sensitivity test, and MDR1, MRP1, and MRP2 mRNA expression in human colorectal adenocarcinomas.Pharm Res. 2004 Mar;21(3):406-12. doi: 10.1023/B:PHAM.0000019292.03875.3e.
5	Increased expression of multidrug resistance-associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin.Int J Cancer. 2002 Apr 1;98(4):630-5. doi: 10.1002/ijc.10246.
6	Expression of the multidrug resistance proteins MRP2 and MRP3 in human cholangiocellular carcinomas.Eur J Clin Invest. 2008 Feb;38(2):134-42. doi: 10.1111/j.1365-2362.2007.01916.x.
7	Immunohistochemical Assessment of the Expression of Biliary Transportation Proteins MRP2 and MRP3 in Hepatocellular Carcinoma and in Cholangiocarcinoma.Pathol Oncol Res. 2019 Oct;25(4):1363-1371. doi: 10.1007/s12253-018-0386-8. Epub 2018 Feb 20.
8	Involvement of ABC transporters in chemosensitivity of human renal cell carcinoma, and regulation of MRP2 expression by conjugated bilirubin.Anticancer Res. 2005 Jul-Aug;25(4):2729-35.
9	The Circadian Clock Gene Bmal1 Controls Intestinal Exporter MRP2 and Drug Disposition.Theranostics. 2019 Apr 13;9(10):2754-2767. doi: 10.7150/thno.33395. eCollection 2019.
10	ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2.Cancer Lett. 2018 Jul 28;427:9-17. doi: 10.1016/j.canlet.2018.04.013. Epub 2018 Apr 13.
11	Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma.Br J Cancer. 2011 Feb 15;104(4):707-13. doi: 10.1038/sj.bjc.6606071. Epub 2011 Jan 4.
12	Changes in Radixin Expression and Interaction with Efflux Transporters in the Liver of Adjuvant-Induced Arthritic Rats.Inflammation. 2020 Feb;43(1):85-94. doi: 10.1007/s10753-019-01097-9.
13	Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection.J Hepatol. 2001 Dec;35(6):765-73. doi: 10.1016/s0168-8278(01)00216-1.
14	Pre-Hepatectomy Assessment of Bile Transporter Expression by Gadoxetic Acid-Enhanced MRI in a Rat Model of Liver Cirrhosis.J Invest Surg. 2017 Aug;30(4):265-271. doi: 10.1080/08941939.2016.1238983. Epub 2016 Oct 26.
15	New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.Biomed Pharmacother. 2017 Dec;96:659-666. doi: 10.1016/j.biopha.2017.10.041. Epub 2017 Nov 6.
16	The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2.Oncotarget. 2015 May 10;6(13):10853-67. doi: 10.18632/oncotarget.3414.
17	Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer.Sci Rep. 2019 Feb 19;9(1):2245. doi: 10.1038/s41598-019-38667-8.
18	Expression of multidrug resistance-associated protein 2 is involved in chemotherapy resistance in human pancreatic cancer.Int J Oncol. 2008 Dec;33(6):1187-94.
19	Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis.J Hepatol. 2003 Jun;38(6):717-27. doi: 10.1016/s0168-8278(03)00096-5.
20	Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response.Clin Cancer Res. 1999 Mar;5(3):673-80.
21	The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype.Iran J Basic Med Sci. 2018 Nov;21(11):1192-1197. doi: 10.22038/IJBMS.2018.29474.7118.
22	A p110-specific inhibitor combined with bortezomib blocks drug resistance properties of EBV-related B cell origin cancer cells via regulation of NF-B.Int J Oncol. 2017 May;50(5):1711-1720. doi: 10.3892/ijo.2017.3923. Epub 2017 Mar 21.
23	Hepatoprotection of auraptene from the peels of citrus fruits against 17-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor.Food Funct. 2019 Jul 17;10(7):3839-3850. doi: 10.1039/c9fo00318e.
24	Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. World J Gastroenterol. 2005 May 14;11(18):2748-53. doi: 10.3748/wjg.v11.i18.2748.
25	Protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells.Int J Cancer. 2005 Jun 20;115(3):393-402. doi: 10.1002/ijc.20899.
26	The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype.Blood. 2003 Dec 15;102(13):4493-8. doi: 10.1182/blood-2002-11-3461. Epub 2003 Jun 19.
27	The phytoestrogens daidzein and equol inhibit the drug transporter BCRP/ABCG2 in breast cancer cells: potential chemosensitizing effect.Eur J Nutr. 2019 Feb;58(1):139-150. doi: 10.1007/s00394-017-1578-9. Epub 2017 Nov 3.
28	A Time-Dependent Model Describes Methotrexate Elimination and Supports Dynamic Modification of MRP2/ABCC2 Activity.Ther Drug Monit. 2017 Apr;39(2):145-156. doi: 10.1097/FTD.0000000000000381.
29	A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine. Pharmacogenomics J. 2014 Oct;14(5):481-7.
30	Expression of multidrug resistance-associated protein 2 in human gallbladder carcinoma.Biomed Res Int. 2013;2013:527534. doi: 10.1155/2013/527534. Epub 2013 Jun 16.
31	The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma.Ann Oncol. 2001 Sep;12(9):1239-45. doi: 10.1023/a:1012292230480.
32	Bile acid transport correlative protein mRNA expression profile in human placenta with intrahepatic cholestasis of pregnancy.Saudi Med J. 2009 Nov;30(11):1406-10.
33	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
34	Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
35	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.
36	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.