Details of Drug Off-Target (DOT)

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

DOT Name	F-box/WD repeat-containing protein 4 (FBXW4)
Synonyms	Dactylin; F-box and WD-40 domain-containing protein 4
Gene Name	FBXW4
Related Disease	Neuroblastoma ( ) Acute monocytic leukemia ( ) Acute myelogenous leukaemia ( ) Bladder cancer ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Cholangiocarcinoma ( ) Clear cell renal carcinoma ( ) Cutaneous leishmaniasis ( ) Esophageal squamous cell carcinoma ( ) Hepatocellular carcinoma ( ) Malignant soft tissue neoplasm ( ) Myelodysplastic syndrome ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Relapsing-remitting multiple sclerosis ( ) Renal cell carcinoma ( ) Rhabdomyosarcoma ( ) Sarcoma ( ) Testicular cancer ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Colon cancer ( ) Colon carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Metastatic malignant neoplasm ( ) Advanced cancer ( ) Hemoglobinopathy ( ) Melanoma ( ) Myeloproliferative neoplasm ( ) Split hand-foot malformation 3 ( )
UniProt ID	FBXW4_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF12937 ; PF00400
Sequence	MAAAAGEEEEEEEAARESAARPAAGPALWRLPEELLLLICSYLDMRALGRLAQVCRWLRR FTSCDLLWRRIARASLNSGFTRLGTDLMTSVPVKERVKVSQNWRLGRCREGILLKWRCSQ MPWMQLEDDSLYISQANFILAYQFRPDGASLNRRPLGVFAGHDEDVCHFVLANSHIVSAG GDGKIGIHKIHSTFTVKYSAHEQEVNCVDCKGGIIVSGSRDRTAKVWPLASGRLGQCLHT IQTEDRVWSIAISPLLSSFVTGTACCGHFSPLRIWDLNSGQLMTHLGSDFPPGAGVLDVM YESPFTLLSCGYDTYVRYWDLRTSVRKCVMEWEEPHDSTLYCLQTDGNHLLATGSSYYGV VRLWDRRQRACLHAFPLTSTPLSSPVYCLRLTTKHLYAALSYNLHVLDFQNP
Function	Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. Likely to be involved in key signaling pathways crucial for normal limb development. May participate in Wnt signaling.
Tissue Specificity	Expressed in brain, kidney, lung and liver.
Reactome Pathway	Neddylation (R-HSA-8951664 ) Antigen processing (R-HSA-983168 ) Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471 )

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Posttranslational Modification	[4]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[5]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Posttranslational Modification	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Cutaneous leishmaniasis	DISRK7TS	Strong	Genetic Variation	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Osteosarcoma	DISLQ7E2	Strong	Posttranslational Modification	[4]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[15]
Sarcoma	DISZDG3U	Strong	Altered Expression	[11]
Testicular cancer	DIS6HNYO	Strong	Altered Expression	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Colon cancer	DISVC52G	moderate	Biomarker	[16]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[16]
Lung cancer	DISCM4YA	moderate	Biomarker	[16]
Lung carcinoma	DISTR26C	moderate	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[16]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[9]
Hemoglobinopathy	DISCT4GX	Limited	Biomarker	[17]
Melanoma	DIS1RRCY	Limited	Biomarker	[18]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[19]
Split hand-foot malformation 3	DISIIYAQ	Limited	Autosomal dominant	[20]
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⏷ Show the Full List of 34 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

6 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 F-box/WD repeat-containing protein 4 (FBXW4).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box/WD repeat-containing protein 4 (FBXW4).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-box/WD repeat-containing protein 4 (FBXW4).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of F-box/WD repeat-containing protein 4 (FBXW4).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of F-box/WD repeat-containing protein 4 (FBXW4).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of F-box/WD repeat-containing protein 4 (FBXW4).	[24]
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⏷ Show the Full List of 6 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the methylation of F-box/WD repeat-containing protein 4 (FBXW4).	[26]
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References

1	Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers.Genome Biol. 2012 Oct 3;13(10):R95. doi: 10.1186/gb-2012-13-10-r95.
2	Early induction intensification with cladribine, cytarabine, and mitoxantrone (CLAM) in AML patients treated with the DAC induction regimen: a prospective, non-randomized, phase II study of the Polish Adult Leukemia Group (PALG).Leuk Lymphoma. 2020 Mar;61(3):588-603. doi: 10.1080/10428194.2019.1678151. Epub 2019 Oct 29.
3	The epigenetically regulated effects of Wnt antagonists on the expression of genes in the apoptosis pathway in human bladder cancer cell line (T24).DNA Cell Biol. 2014 Jul;33(7):408-17. doi: 10.1089/dna.2013.2285. Epub 2014 Mar 25.
4	Activation of Estrogen Receptor Alpha by Decitabine Inhibits Osteosarcoma Growth and Metastasis.Cancer Res. 2019 Mar 15;79(6):1054-1068. doi: 10.1158/0008-5472.CAN-18-1255. Epub 2018 Dec 28.
5	Integrated epigenetics of human breast cancer: synoptic investigation of targeted genes, microRNAs and proteins upon demethylation treatment.PLoS One. 2011;6(11):e27355. doi: 10.1371/journal.pone.0027355. Epub 2011 Nov 4.
6	Targeted drug regulation on methylation of p53-BAX mitochondrial apoptosis pathway affects the growth of cholangiocarcinoma cells.J Int Med Res. 2012;40(1):67-75. doi: 10.1177/147323001204000107.
7	DNA methyltransferase inhibitor-mediated apoptosis in the Wnt/-catenin signal pathway in a renal cell carcinoma cell line.Exp Biol Med (Maywood). 2013 Sep;238(9):1009-16. doi: 10.1177/1535370213498984. Epub 2013 Aug 23.
8	Salvage therapy with Sodium chlorosum (formerly DAC N-055) for cases of refractory lupoid cutaneous leishmaniasis: results from a compassionate use study with 0.09% Sodium chlorosum in amphiphilic basic cream.BMC Infect Dis. 2019 Nov 28;19(1):1005. doi: 10.1186/s12879-019-4518-x.
9	Decitabine enhances tumor recognition by T cells through upregulating the MAGE-A3 expression in esophageal carcinoma.Biomed Pharmacother. 2019 Apr;112:108632. doi: 10.1016/j.biopha.2019.108632. Epub 2019 Feb 20.
10	Upregulation of miR-362-3p Modulates Proliferation and Anchorage-Independent Growth by Directly Targeting Tob2 in Hepatocellular Carcinoma.J Cell Biochem. 2015 Aug;116(8):1563-73. doi: 10.1002/jcb.25110.
11	Decitabine facilitates immune recognition of sarcoma cells by upregulating CT antigens, MHC molecules, and ICAM-1.Tumour Biol. 2014 Jun;35(6):5753-62. doi: 10.1007/s13277-014-1764-9. Epub 2014 Mar 2.
12	Establishment and molecular characterization of decitabine-resistant K562 cells.J Cell Mol Med. 2019 May;23(5):3317-3324. doi: 10.1111/jcmm.14221. Epub 2019 Feb 22.
13	The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers.PLoS One. 2013 May 2;8(5):e63610. doi: 10.1371/journal.pone.0063610. Print 2013.
14	Daclizumab and its use in multiple sclerosis treatment.Drugs Today (Barc). 2017 Jan;53(1):7-18. doi: 10.1358/dot.2017.53.1.2570979.
15	Therapeutic differentiation in a human rhabdomyosarcoma cell line selected for resistance to actinomycin D.Int J Cancer. 1998 Jan 30;75(3):379-83. doi: 10.1002/(sici)1097-0215(19980130)75:3<379::aid-ijc9>3.0.co;2-#.
16	DAC can restore expression of NALP1 to suppress tumor growth in colon cancer.Cell Death Dis. 2015 Jan 22;6(1):e1602. doi: 10.1038/cddis.2014.532.
17	In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies.Ann Hematol. 2005 Dec;84 Suppl 1:32-8. doi: 10.1007/s00277-005-0004-1.
18	Combining Type I Interferons and 5-Aza-2'-Deoxycitidine to Improve Anti-Tumor Response against Melanoma.J Invest Dermatol. 2017 Jan;137(1):159-169. doi: 10.1016/j.jid.2016.08.024. Epub 2016 Sep 10.
19	Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients.Am J Hematol. 2019 Jul;94(7):767-779. doi: 10.1002/ajh.25488. Epub 2019 May 3.
20	Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
21	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
22	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
23	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
24	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.
25	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.
26	DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study. Toxicol Lett. 2014 Dec 1;231(2):217-26. doi: 10.1016/j.toxlet.2014.10.024. Epub 2014 Oct 22.