Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHLPHA0)

• DOT Name: Chemokine-like factor (CKLF)
• Synonyms: C32
• Gene Name: CKLF
• Related Disease:
  Multiple sclerosis
  Advanced cancer
  Atopic dermatitis
  Cerebral infarction
  Colorectal carcinoma
  Dermatomyositis
  Idiopathic inflammatory myopathy
  Myositis disease
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Pneumonitis
  Polymyositis
  Psoriasis
  Schizophrenia
  Severe acute respiratory syndrome (SARS)
  Stroke
  Asthma
  Cervical carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
• UniProt ID: CKLF_HUMAN
• Sequence:
  MDNVQPKIKHRPFCFSVKGHVKMLRLALTVTSMTFFIIAQAPEPYIVITGFEVTVILFFI
  LLYVLRLDRLMKWLFWPLLDIINSLVTTVFMLIVSVLALIPETTTLTVGGGVFALVTAVC
  CLADGALIYRKLLFNPSGPYQKKPVHEKKEVL
• Function: May play an important role in inflammation and regeneration of skeletal muscle. Essential for embryonic development; [Isoform 1]: Has chemotactic response in monocytes, neutrophils and lymphocytes. Binds CCR4.
• Tissue Specificity: Isoform 1, isoform 2, isoform 3 and isoform 4 have highest expression levels in adult spleen, lung, testis, ovary, peripheral blood leukocyte, placenta, pancreas, and in fetal brain, skeletal muscle, thymus and heart. Lower expression levels in adult skeletal muscle, liver, thymus colon, prostate and fetal spleen and liver.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[3]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Dermatomyositis	DIS50C5O	Strong	Altered Expression	[6]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Altered Expression	[6]
Myositis disease	DISCIXF0	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Pneumonitis	DIS88E0K	Strong	Biomarker	[9]
Polymyositis	DIS5DHFP	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Severe acute respiratory syndrome (SARS)	DISYW14W	Strong	Biomarker	[9]
Stroke	DISX6UHX	Strong	Biomarker	[12]
Asthma	DISW9QNS	moderate	Biomarker	[13]
Cervical carcinoma	DIST4S00	moderate	Posttranslational Modification	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[2]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Chemokine-like factor (CKLF) affects the response to substance of Mitoxantrone.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Chemokine-like factor (CKLF).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chemokine-like factor (CKLF).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chemokine-like factor (CKLF).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chemokine-like factor (CKLF).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Chemokine-like factor (CKLF).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Chemokine-like factor (CKLF).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Chemokine-like factor (CKLF).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Chemokine-like factor (CKLF).	[22]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Chemokine-like factor (CKLF).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chemokine-like factor (CKLF).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Chemokine-like factor (CKLF).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Chemokine-like factor (CKLF).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Chemokine-like factor (CKLF).	[28]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Chemokine-like factor (CKLF).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chemokine-like factor (CKLF).	[24]

References

• [1] Discovery and optimization of novel 3-piperazinylcoumarin antagonist of chemokine-like factor 1 with oral antiasthma activity in mice.J Med Chem. 2010 Feb 25;53(4):1741-54. doi: 10.1021/jm901652p.
• [2] CKLF1 Enhances Inflammation-Mediated Carcinogenesis and Prevents Doxorubicin-Induced Apoptosis via IL6/STAT3 Signaling in HCC.Clin Cancer Res. 2019 Jul 1;25(13):4141-4154. doi: 10.1158/1078-0432.CCR-18-3510. Epub 2019 Mar 27.
• [3] Chemokine-like factor 1 (CLFK1) is over-expressed in patients with atopic dermatitis.Int J Biol Sci. 2013 Aug 13;9(8):759-65. doi: 10.7150/ijbs.6291. eCollection 2013.
• [4] CKLF1 Aggravates Focal Cerebral Ischemia Injury at Early Stage Partly by Modulating Microglia/Macrophage Toward M1 Polarization Through CCR4.Cell Mol Neurobiol. 2019 Jul;39(5):651-669. doi: 10.1007/s10571-019-00669-5. Epub 2019 Apr 13.
• [5] Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer.Oncotarget. 2016 Jun 14;7(24):36632-36644. doi: 10.18632/oncotarget.9126.
• [6] Chemokine-like factor expression in the idiopathic inflammatory myopathies.Acta Neurol Scand. 2008 Aug;118(2):106-14. doi: 10.1111/j.1600-0404.2007.00990.x. Epub 2008 Feb 19.
• [7] Research Advances in CKLF-like MARVEL Transmembrane Domain-containing Family in Non-small Cell Lung Cancer.Int J Biol Sci. 2019 Sep 7;15(12):2576-2583. doi: 10.7150/ijbs.33733. eCollection 2019.
• [8] CMTM5 induces apoptosis of pancreatic cancer cells and has synergistic effects with TNF-alpha.Biochem Biophys Res Commun. 2009 Sep 11;387(1):139-42. doi: 10.1016/j.bbrc.2009.06.148. Epub 2009 Jul 3.
• [9] Chemokine-like factor 1, a novel cytokine, contributes to airway damage, remodeling and pulmonary fibrosis.Chin Med J (Engl). 2004 Aug;117(8):1123-9.
• [10] C19, a C-terminal peptide of CKLF1, decreases inflammation and proliferation of dermal capillaries in psoriasis.Sci Rep. 2017 Oct 24;7(1):13890. doi: 10.1038/s41598-017-13799-x.
• [11] Genome-wide association study identifies five new schizophrenia loci.Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940.
• [12] IMM-H004 Protects against Cerebral Ischemia Injury and Cardiopulmonary Complications via CKLF1 Mediated Inflammation Pathway in Adult and Aged Rats.Int J Mol Sci. 2019 Apr 3;20(7):1661. doi: 10.3390/ijms20071661.
• [13] The chemokine-like factor 1 induces asthmatic pathological change by activating nuclear factor-B signaling pathway.Int Immunopharmacol. 2014 May;20(1):81-8. doi: 10.1016/j.intimp.2014.02.014. Epub 2014 Feb 25.
• [14] CMTM5-v1 induces apoptosis in cervical carcinoma cells.Biochem Biophys Res Commun. 2009 Feb 20;379(4):866-71. doi: 10.1016/j.bbrc.2008.12.126. Epub 2009 Jan 3.
• [15] Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma.Anticancer Res. 2016 Aug;36(8):4013-8.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [21] 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.
• [22] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [23] 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.
• [24] 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.
• [25] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [26] 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.
• [27] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.