Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC2T1MP)

• DOT Name: Leucine-rich repeat neuronal protein 4 (LRRN4)
• Synonyms: Neuronal leucine-rich repeat protein 4; NLRR-4
• Gene Name: LRRN4
• Related Disease:
  Mesothelioma
  Obesity
• UniProt ID: LRRN4_HUMAN
• Pfam ID: PF00041 ; PF13855
• Sequence:
  MRQTLPLLLLTVLRPSWADPPQEKVPLFRVTQQGPWGSSGSNATDSPCEGLPAADATALT
  LANRNLERLPGCLPRTLRSLDASHNLLRALSTSELGHLEQLQVLTLRHNRIAALRWGPGG
  PAGLHTLDLSYNQLAALPPCTGPALSSLRALALAGNPLRALQPRAFACFPALQLLNLSCT
  ALGRGAQGGIAEAAFAGEDGAPLVTLEVLDLSGTFLERVESGWIRDLPKLTSLYLRKMPR
  LTTLEGDIFKMTPNLQQLDCQDSPALASVATHIFQDTPHLQVLLFQNCNLSSFPPWTLDS
  SQVLSINLFGNPLTCSCDLSWLLTDAKRTVLSRAADTMCAPAAGSSGPFSASLSLSQLPG
  VCQSDQSTTLGASHPPCFNRSTYAQGTTVAPSAAPATRPAGDQQSVSKAPNVGSRTIAAW
  PHSDAREGTAPSTTNSVAGHSNSSVFPRAASTTRTQHRGEHAPELVLEPDISAASTPLAS
  KLLGPFPTSWDRSISSPQPGQRTHATPQAPNPSLSEGEIPVLLLDDYSEEEEGRKEEVGT
  PHQDVPCDYHPCKHLQTPCAELQRRWRCRCPGLSGEDTIPDPPRLQGVTETTDTSALVHW
  CAPNSVVHGYQIRYSAEGWAGNQSVVGVIYATARQHPLYGLSPGTTYRVCVLAANRAGLS
  QPRSSGWRSPCAAFTTKPSFALLLSGLCAASGLLLASTVVLSACLCRRGQTLGLQRCDTH
  LVAYKNPAFDDYPLGLQTVS
• Function: May play an important role in hippocampus-dependent long-lasting memory.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mesothelioma	DISKWK9M	Strong	Biomarker	[1]
Obesity	DIS47Y1K	Strong	Genetic Variation	[2]

2 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 neuronal protein 4 (LRRN4).	[3]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the methylation of Leucine-rich repeat neuronal protein 4 (LRRN4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat neuronal protein 4 (LRRN4).	[13]

References

• [1] LRRN4 and UPK3B are markers of primary mesothelial cells.PLoS One. 2011;6(10):e25391. doi: 10.1371/journal.pone.0025391. Epub 2011 Oct 3.
• [2] Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants.PLoS One. 2007 Dec 26;2(12):e1361. doi: 10.1371/journal.pone.0001361.
• [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] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] 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.