Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEJ5MO0)

• DOT Name: F-box only protein 22 (FBXO22)
• Synonyms: F-box protein FBX22p44
• Gene Name: FBXO22
• Related Disease:
  Breast neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Gout
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Renal cell carcinoma
  Neoplasm
• UniProt ID: FBX22_HUMAN
• Pfam ID: PF00646 ; PF10442
• Sequence:
  MEPVGCCGECRGSSVDPRSTFVLSNLAEVVERVLTFLPAKALLRVACVCRLWRECVRRVL
  RTHRSVTWISAGLAEAGHLEGHCLVRVVAEELENVRILPHTVLYMADSETFISLEECRGH
  KRARKRTSMETALALEKLFPKQCQVLGIVTPGIVVTPMGSGSNRPQEIEIGESGFALLFP
  QIEGIKIQPFHFIKDPKNLTLERHQLTEVGLLDNPELRVVLVFGYNCCKVGASNYLQQVV
  STFSDMNIILAGGQVDNLSSLTSEKNPLDIDASGVVGLSFSGHRIQSATVLLNEDVSDEK
  TAEAAMQRLKAANIPEHNTIGFMFACVGRGFQYYRAKGNVEADAFRKFFPSVPLFGFFGN
  GEIGCDRIVTGNFILRKCNEVKDDDLFHSYTTIMALIHLGSSK
• Function: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin (ACTN2) and filamin-C (FLNC), essential for maintenance of normal contractile function.
• Tissue Specificity: Predominantly expressed in liver, also enriched in cardiac muscle.
• KEGG Pathway: Salmonella infection (hsa05132)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Gout	DISHC0U7	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of F-box only protein 22 (FBXO22).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box only protein 22 (FBXO22).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box only protein 22 (FBXO22).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of F-box only protein 22 (FBXO22).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of F-box only protein 22 (FBXO22).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box only protein 22 (FBXO22).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of F-box only protein 22 (FBXO22).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of F-box only protein 22 (FBXO22).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of F-box only protein 22 (FBXO22).	[14]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of F-box only protein 22 (FBXO22).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of F-box only protein 22 (FBXO22).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of F-box only protein 22 (FBXO22).	[7]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of F-box only protein 22 (FBXO22).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of F-box only protein 22 (FBXO22).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of F-box only protein 22 (FBXO22).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of F-box only protein 22 (FBXO22).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of F-box only protein 22 (FBXO22).	[18]

References

• [1] SCF(FBXO22) targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis.Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11754-11763. doi: 10.1073/pnas.1820990116. Epub 2019 May 28.
• [2] FBXO22 Suppresses Metastasis in Human Renal Cell Carcinoma via Inhibiting MMP-9-Mediated Migration and Invasion and VEGF-Mediated Angiogenesis.Int J Biol Sci. 2019 Jan 24;15(3):647-656. doi: 10.7150/ijbs.31293. eCollection 2019.
• [3] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [4] FBXO22 promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21.J Exp Clin Cancer Res. 2019 Feb 26;38(1):101. doi: 10.1186/s13046-019-1058-6.
• [5] FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth.Cell Death Dis. 2019 Jun 19;10(7):486. doi: 10.1038/s41419-019-1732-9.
• [6] Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1/VEGF pathway.Invest New Drugs. 2020 Feb;38(1):20-28. doi: 10.1007/s10637-019-00761-z. Epub 2019 Mar 18.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] 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.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.