Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7RWBKE)

• DOT Name: Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4)
• Gene Name: LRFN4
• Related Disease:
  Epilepsy
  Status epilepticus seizure
  Gastric cancer
  Neoplasm
  Stomach cancer
• UniProt ID: LRFN4_HUMAN
• Pfam ID: PF00041 ; PF07679 ; PF00560 ; PF13855
• Sequence:
  MAPPLLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADNFI
  QALGPPDFRNMTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSLRGPV
  NLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVPWAGIGAMPALHTLNLDHNL
  IDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFSGNPLHCNC
  ELLWLRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRLWVLEGQRATL
  RCRALGDPAPTMHWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGGYTCIATNPAGEA
  TARVELRVLALPHGGNSSAEGGRPGPSDIAASARTAAEGEGTLESEPAVQVTEVTATSGL
  VSWGPGRPADPVWMFQIQYNSSEDETLIYRIVPASSHHFLLKHLVPGADYDLCLLALSPA
  AGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAVGGVLVAALLVFTVALLVR
  GRGAGNGRLPLKLSHVQSQTNGGPSPTPKAHPPRSPPPRPQRSCSLDLGDAGCYGYARRL
  GGAWARRSHSVHGGLLGAGCRGVGGSAERLEESVV
• Function: Promotes neurite outgrowth in hippocampal neurons. May play a role in redistributing DLG4 to the cell periphery.
• Reactome Pathway: Synaptic adhesion-like molecules (R-HSA-8849932)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Disputed	Altered Expression	[2]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[2]
Stomach cancer	DISKIJSX	Disputed	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[3]

10 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 Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Leucine-rich repeat and fibronectin type-III domain-containing protein 4 (LRFN4).	[13]

References

• [1] Effect of synaptic adhesion-like molecule 3 on epileptic seizures: Evidence from animal models.Epilepsy Behav. 2017 Apr;69:18-23. doi: 10.1016/j.yebeh.2016.11.023. Epub 2017 Mar 14.
• [2] High SALM3 Expression in Tumor Cells and Fibroblasts Is Correlated with Poor Prognosis in Gastric Cancer Patients.Dis Markers. 2019 Apr 4;2019:8282414. doi: 10.1155/2019/8282414. eCollection 2019.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] 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.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.