Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3YVA0)

• DOT Name: Krueppel-like factor 7 (KLF7)
• Synonyms: Ubiquitous krueppel-like factor
• Gene Name: KLF7
• Related Disease:
  Autism
  Cone-rod dystrophy 2
  Glioma
  Metabolic disorder
  Non-small-cell lung cancer
  Obesity
  Gastric cancer
  Intellectual disability
  Stomach cancer
  Squamous cell carcinoma
• UniProt ID: KLF7_HUMAN
• Pfam ID: PF00096
• Sequence:
  MDVLASYSIFQELQLVHDTGYFSALPSLEETWQQTCLELERYLQTEPRRISETFGEDLDC
  FLHASPPPCIEESFRRLDPLLLPVEAAICEKSSAVDILLSRDKLLSETCLSLQPASSSLD
  SYTAVNQAQLNAVTSLTPPSSPELSRHLVKTSQTLSAVDGTVTLKLVAKKAALSSVKVGG
  VATAAAAVTAAGAVKSGQSDSDQGGLGAEACPENKKRVHRCQFNGCRKVYTKSSHLKAHQ
  RTHTGEKPYKCSWEGCEWRFARSDELTRHYRKHTGAKPFKCNHCDRCFSRSDHLALHMKR
  HI
• Function: Transcriptional factor. Plays a critical role in neuronal morphogenesis and survival of sensory neurons. Represses the corneal epithelium differentiation. Acts also as a metabolic regulator, by modulating insulin sensitivity in pancreatic beta cells and skeletal muscle cells. Inhibits transcriptional inducers of adipogenesis and has a repressive role in the expression of several adipokines, including leptin.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Biomarker	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Obesity	DIS47Y1K	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[7]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[1]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[8]

17 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 Krueppel-like factor 7 (KLF7).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Krueppel-like factor 7 (KLF7).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Krueppel-like factor 7 (KLF7).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Krueppel-like factor 7 (KLF7).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Krueppel-like factor 7 (KLF7).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Krueppel-like factor 7 (KLF7).	[14]
Morphine	DMRMS0L	Approved	Morphine increases the expression of Krueppel-like factor 7 (KLF7).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Krueppel-like factor 7 (KLF7).	[16]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Krueppel-like factor 7 (KLF7).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Krueppel-like factor 7 (KLF7).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Krueppel-like factor 7 (KLF7).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Krueppel-like factor 7 (KLF7).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Krueppel-like factor 7 (KLF7).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Krueppel-like factor 7 (KLF7).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Krueppel-like factor 7 (KLF7).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Krueppel-like factor 7 (KLF7).	[26]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Krueppel-like factor 7 (KLF7).	[27]

2 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 affects the methylation of Krueppel-like factor 7 (KLF7).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Krueppel-like factor 7 (KLF7).	[21]

References

• [1] De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability, neuromuscular and psychiatric symptoms.Clin Genet. 2018 May;93(5):1030-1038. doi: 10.1111/cge.13198. Epub 2018 Jan 25.
• [2] AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury.Neural Plast. 2017;2017:1621629. doi: 10.1155/2017/1621629. Epub 2017 Aug 13.
• [3] KLF7 promotes polyamine biosynthesis and glioma development through transcriptionally activating ASL.Biochem Biophys Res Commun. 2019 Jun 18;514(1):51-57. doi: 10.1016/j.bbrc.2019.04.120. Epub 2019 Apr 21.
• [4] Loss of the third C2H2 zinc finger of chicken KLF7 affects its transcriptional regulation activities in adipose tissue.Acta Biochim Biophys Sin (Shanghai). 2020 Jan 2;52(1):84-90. doi: 10.1093/abbs/gmz132.
• [5] miR-185 Inhibits the Proliferation and Invasion of Non-Small Cell Lung Cancer by Targeting KLF7.Oncol Res. 2019 Sep 23;27(9):1015-1023. doi: 10.3727/096504018X15247341491655. Epub 2018 May 1.
• [6] Correlation of TLR4 and KLF7 in Inflammation Induced by Obesity.Inflammation. 2017 Feb;40(1):42-51. doi: 10.1007/s10753-016-0450-z.
• [7] Krppel-Like Factor 7 is a Marker of Aggressive Gastric Cancer and Poor Prognosis.Cell Physiol Biochem. 2017;43(3):1090-1099. doi: 10.1159/000481748. Epub 2017 Oct 5.
• [8] KLF7 overexpression in human oral squamous cell carcinoma promotes migration and epithelial-mesenchymal transition.Oncol Lett. 2017 Apr;13(4):2281-2289. doi: 10.3892/ol.2017.5734. Epub 2017 Feb 13.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [15] Identification of opioid-regulated genes in human lymphocytic cells by differential display: upregulation of Krppel-like factor 7 by morphine. Exp Cell Res. 2003 Dec 10;291(2):340-51. doi: 10.1016/s0014-4827(03)00408-7.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005 Jun 15;11(12):4610-9.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [23] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.