Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7XJ70N)

• DOT Name: Leucine-rich repeat-containing protein 4 (LRRC4)
• Synonyms: Brain tumor-associated protein BAG; Nasopharyngeal carcinoma-associated gene 14 protein; Netrin-G2 ligand; NGL-2
• Gene Name: LRRC4
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Autism spectrum disorder
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Castration-resistant prostate carcinoma
  Colitis
  Cystic fibrosis
  Cytomegalovirus infection
  Epilepsy syndrome
  Glioma
  Kidney cancer
  Pervasive developmental disorder
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Schizophrenia
  Sleep apnea syndrome
  Stroke
  Dedifferentiated liposarcoma
  Glioblastoma multiforme
  Meningioma
  Nasopharyngeal carcinoma
  Nasopharyngeal disorder
  Nasopharyngitis
  Neoplasm
  Neuroblastoma
  Osteomyelitis
  Tuberculosis
  Young-onset Parkinson disease
• UniProt ID: LRRC4_HUMAN
• PDB ID: 2DL9; 3ZYI
• Pfam ID: PF07679 ; PF13855
• Sequence:
  MKLLWQVTVHHHTWNAILLPFVYLTAQVWILCAAIAAAASAGPQNCPSVCSCSNQFSKVV
  CTRRGLSEVPQGIPSNTRYLNLMENNIQMIQADTFRHLHHLEVLQLGRNSIRQIEVGAFN
  GLASLNTLELFDNWLTVIPSGAFEYLSKLRELWLRNNPIESIPSYAFNRVPSLMRLDLGE
  LKKLEYISEGAFEGLFNLKYLNLGMCNIKDMPNLTPLVGLEELEMSGNHFPEIRPGSFHG
  LSSLKKLWVMNSQVSLIERNAFDGLASLVELNLAHNNLSSLPHDLFTPLRYLVELHLHHN
  PWNCDCDILWLAWWLREYIPTNSTCCGRCHAPMHMRGRYLVEVDQASFQCSAPFIMDAPR
  DLNISEGRMAELKCRTPPMSSVKWLLPNGTVLSHASRHPRISVLNDGTLNFSHVLLSDTG
  VYTCMVTNVAGNSNASAYLNVSTAELNTSNYSFFTTVTVETTEISPEDTTRKYKPVPTTS
  TGYQPAYTTSTTVLIQTTRVPKQVAVPATDTTDKMQTSLDEVMKTTKIIIGCFVAVTLLA
  AAMLIVFYKLRKRHQQRSTVTAARTVEIIQVDEDIPAATSAAATAAPSGVSGEGAVVLPT
  IHDHINYNTYKPAHGAHWTENSLGNSLHPTVTTISEPYIIQTHTKDKVQETQI
• Function: Synaptic adhesion protein. Regulates the formation of exitatory synapses through the recruitment of pre-and-postsynaptic proteins. Organize the lamina/pathway-specific differentiation of dendrites. Plays an important role for auditory synaptic responses. Involved in the suppression of glioma.
• Tissue Specificity: Specifically expressed in brain.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Cell adhesion molecules (hsa04514)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[6]
Colitis	DISAF7DD	Strong	Altered Expression	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[8]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[9]
Epilepsy syndrome	DISLYXJ3	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Kidney cancer	DISBIPKM	Strong	Biomarker	[12]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Renal carcinoma	DISER9XT	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Sleep apnea syndrome	DISER6KS	Strong	Genetic Variation	[10]
Stroke	DISX6UHX	Strong	Biomarker	[14]
Dedifferentiated liposarcoma	DISYJUCJ	moderate	Biomarker	[15]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[16]
Meningioma	DISPT4TG	moderate	Altered Expression	[17]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[18]
Nasopharyngeal disorder	DISZHFZ9	moderate	Biomarker	[18]
Nasopharyngitis	DISVLL0V	moderate	Biomarker	[18]
Neoplasm	DISZKGEW	moderate	Biomarker	[16]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[19]
Osteomyelitis	DIS0VUZL	Limited	Biomarker	[20]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[21]
Young-onset Parkinson disease	DIS05LFS	Limited	Biomarker	[22]

10 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 Leucine-rich repeat-containing protein 4 (LRRC4).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[26]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[31]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Leucine-rich repeat-containing protein 4 (LRRC4).	[32]

1 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 increases the methylation of Leucine-rich repeat-containing protein 4 (LRRC4).	[29]

References

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• [2] BAG-1M co-activates BACE1 transcription through NF-B and accelerates A production and memory deficit in Alzheimer's disease mouse model.Biochim Biophys Acta Mol Basis Dis. 2017 Sep;1863(9):2398-2407. doi: 10.1016/j.bbadis.2017.05.014. Epub 2017 May 11.
• [3] Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features. Neurogenetics. 2019 Oct;20(4):209-213. doi: 10.1007/s10048-019-00583-4. Epub 2019 Aug 2.
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• [8] Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy.J Biol Chem. 2018 Aug 31;293(35):13682-13695. doi: 10.1074/jbc.RA118.002607. Epub 2018 Jul 9.
• [9] Evaluation of the AmpliSensor PCR and the SHARP signal detection system for the early prediction of symptomatic CMV infection in solid transplant recipients.J Clin Virol. 1999 Jun;13(1-2):81-94. doi: 10.1016/s1386-6532(99)00013-x.
• [10] Obstructive sleep apnea in refractory epilepsy: A pilot study investigating frequency, clinical features, and association with risk of sudden unexpected death in epilepsy.Epilepsia. 2018 Oct;59(10):1973-1981. doi: 10.1111/epi.14548. Epub 2018 Sep 24.
• [11] Function and mechanism of tumor suppressor gene LRRC4/NGL-2.Mol Cancer. 2014 Dec 19;13:266. doi: 10.1186/1476-4598-13-266.
• [12] Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expression.Br J Pharmacol. 2009 Nov;158(5):1405-12. doi: 10.1111/j.1476-5381.2009.00455.x. Epub 2009 Aug 13.
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• [15] Identification of Coiled-Coil Domain-Containing Protein 180 and Leucine-Rich Repeat-Containing Protein 4 as Potential Immunohistochemical Markers for Liposarcoma Based on Proteomic Analysis Using Formalin-Fixed, Paraffin-Embedded Tissue.Am J Pathol. 2019 May;189(5):1015-1028. doi: 10.1016/j.ajpath.2019.01.013. Epub 2019 Feb 18.
• [16] Novel Therapy for Glioblastoma Multiforme by Restoring LRRC4 in Tumor Cells: LRRC4 Inhibits Tumor-Infitrating Regulatory T Cells by Cytokine and Programmed Cell Death 1-Containing Exosomes.Front Immunol. 2017 Dec 11;8:1748. doi: 10.3389/fimmu.2017.01748. eCollection 2017.
• [17] LRRC4 haplotypes are associated with pituitary adenoma in a Chinese population.Med Oncol. 2014 Apr;31(4):888. doi: 10.1007/s12032-014-0888-5. Epub 2014 Feb 23.
• [18] Expression and clinical significance of LRRC4 in benign and malignant nasopharyngeal diseases.Genet Mol Res. 2015 Dec 9;14(4):16403-9. doi: 10.4238/2015.December.9.9.
• [19] BAG-1L Protects SH-SY5Y Neuroblastoma Cells Against Hypoxia/Re-oxygenation Through Up-Regulating HSP70 and Activating PI3K/AKT Signaling Pathway.Neurochem Res. 2017 Oct;42(10):2861-2868. doi: 10.1007/s11064-017-2304-y. Epub 2017 May 18.
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• [21] Evaluation of the hyplex TBC PCR test for detection of Mycobacterium tuberculosis complex in clinical samples.BMC Microbiol. 2010 Mar 31;10:95. doi: 10.1186/1471-2180-10-95.
• [22] BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.Neuron. 2004 Dec 16;44(6):931-45. doi: 10.1016/j.neuron.2004.11.026.
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• [24] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
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• [29] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [30] 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.
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• [32] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.