Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB9AVQ4)

• DOT Name: Kit ligand (KITLG)
• Synonyms: Mast cell growth factor; MGF; Stem cell factor; SCF; c-Kit ligand
• Gene Name: KITLG
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss 69
  Autosomal dominant nonsyndromic hearing loss
  Familial progressive hyper- and hypopigmentation
  Familial progressive hyperpigmentation
  Waardenburg syndrome type 2
  Nonsyndromic genetic hearing loss
  Waardenburg syndrome, IIa 2F
• UniProt ID: SCF_HUMAN
• PDB ID: 1EXZ; 1SCF; 2E9W; 8DFM; 8DFP; 8DFQ
• Pfam ID: PF02404
• Sequence:
  MKKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPG
  MDVLPSHCWISEMVVQLSDSLTDLLDKFSNISEGLSNYSIIDKLVNIVDDLVECVKENSS
  KDLKKSFKSPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVT
  KPFMLPPVAASSLRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGALYWKKR
  QPSLTRAVENIQINEEDNEISMLQEKEREFQEV
• Function: Ligand for the receptor-type protein-tyrosine kinase KIT. Plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Phospholipase D sig.ling pathway (hsa04072)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hematopoietic cell lineage (hsa04640)
  Melanogenesis (hsa04916)
  Pathways in cancer (hsa05200)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss 69	DISNZUWP	Strong	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[2]
Familial progressive hyper- and hypopigmentation	DIS891VG	Supportive	Autosomal dominant	[3]
Familial progressive hyperpigmentation	DISVYG2G	Supportive	Autosomal dominant	[4]
Waardenburg syndrome type 2	DISVZBEV	Supportive	Autosomal dominant	[2]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[5]
Waardenburg syndrome, IIa 2F	DIS23EW8	Limited	Unknown	[2]

37 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 Kit ligand (KITLG).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kit ligand (KITLG).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kit ligand (KITLG).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kit ligand (KITLG).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kit ligand (KITLG).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kit ligand (KITLG).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kit ligand (KITLG).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Kit ligand (KITLG).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kit ligand (KITLG).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kit ligand (KITLG).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Kit ligand (KITLG).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Kit ligand (KITLG).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kit ligand (KITLG).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Kit ligand (KITLG).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Kit ligand (KITLG).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Kit ligand (KITLG).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Kit ligand (KITLG).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Kit ligand (KITLG).	[22]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Kit ligand (KITLG).	[23]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Kit ligand (KITLG).	[24]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Kit ligand (KITLG).	[25]
Oxymetholone	DMFXUT8	Approved	Oxymetholone increases the expression of Kit ligand (KITLG).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kit ligand (KITLG).	[27]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Kit ligand (KITLG).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kit ligand (KITLG).	[16]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Kit ligand (KITLG).	[28]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Kit ligand (KITLG).	[29]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Kit ligand (KITLG).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kit ligand (KITLG).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kit ligand (KITLG).	[32]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Kit ligand (KITLG).	[33]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha decreases the expression of Kit ligand (KITLG).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kit ligand (KITLG).	[34]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Kit ligand (KITLG).	[36]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Kit ligand (KITLG).	[37]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the expression of Kit ligand (KITLG).	[22]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate affects the expression of Kit ligand (KITLG).	[38]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the secretion of Kit ligand (KITLG).	[35]

References

• [1] TRP-2/DT, a new early melanoblast marker, shows that steel growth factor (c-kit ligand) is a survival factor. Development. 1992 Aug;115(4):1111-9. doi: 10.1242/dev.115.4.1111.
• [2] Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2. Am J Hum Genet. 2015 Nov 5;97(5):647-60. doi: 10.1016/j.ajhg.2015.09.011. Epub 2015 Oct 29.
• [3] KITLG mutations cause familial progressive hyper- and hypopigmentation. J Invest Dermatol. 2011 Jun;131(6):1234-9. doi: 10.1038/jid.2011.29. Epub 2011 Mar 3.
• [4] Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. Am J Hum Genet. 2009 May;84(5):672-7. doi: 10.1016/j.ajhg.2009.03.019. Epub 2009 Apr 16.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [12] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [13] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [14] 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.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] 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.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. J Biol Chem. 2009 Feb 13;284(7):4343-53. doi: 10.1074/jbc.M805570200. Epub 2008 Dec 18.
• [21] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [22] How benzene and its metabolites affect human marrow derived mesenchymal stem cells. Toxicol Lett. 2012 Oct 17;214(2):145-53. doi: 10.1016/j.toxlet.2012.08.015. Epub 2012 Aug 30.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [25] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [26] Direct and indirect effects of androgens on survival of hematopoietic progenitor cells in vitro. J Korean Med Sci. 2005 Jun;20(3):409-16. doi: 10.3346/jkms.2005.20.3.409.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [29] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [30] Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses. J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.
• [31] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [34] 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.
• [35] Ni(II) ions dysregulate cytokine secretion from human monocytes. J Biomed Mater Res B Appl Biomater. 2009 Feb;88(2):358-65. doi: 10.1002/jbm.b.31063.
• [36] Cytokine responses of intestinal epithelial-like Caco-2 cells to non-pathogenic and opportunistic pathogenic yeasts in the presence of butyric acid. Biosci Biotechnol Biochem. 2007 Oct;71(10):2428-34.
• [37] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.
• [38] Gene profiles of a human alveolar epithelial cell line after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol Lett. 2009 Feb 25;185(1):16-22. doi: 10.1016/j.toxlet.2008.11.017. Epub 2008 Dec 6.