Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJFA4AV)

• DOT Name: Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4)
• Synonyms: Leucine-rich repeat neuronal protein 4; Leucine-rich neuronal protein
• Gene Name: LRCH4
• Related Disease: Inflammation
• UniProt ID: LRCH4_HUMAN
• Pfam ID: PF00307 ; PF13855
• Sequence:
  MAAAVAAPLAAGGEEAAATTSVPGSPGLPGRRSAERALEEAVATGTLNLSNRRLKHFPRG
  AARSYDLSDITQADLSRNRFPEVPEAACQLVSLEGLSLYHNCLRCLNPALGNLTALTYLN
  LSRNQLSLLPPYICQLPLRVLIVSNNKLGALPPDIGTLGSLRQLDVSSNELQSLPSELCG
  LSSLRDLNVRRNQLSTLPEELGDLPLVRLDFSCNRVSRIPVSFCRLRHLQVILLDSNPLQ
  SPPAQVCLKGKLHIFKYLSTEAGQRGSALGDLAPSRPPSFSPCPAEDLFPGHRYDGGLDS
  GFHSVDSGSKRWSGNESTDEFSELSFRISELAREPRGPRERKEDGSADGDPVQIDFIDSH
  VPGEDEERGTVEEQRPPELSPGAGDRERAPSSRREEPAGEERRRPDTLQLWQERERRQQQ
  QSGAWGAPRKDSLLKPGLRAVVGGAAAVSTQAMHNGSPKSSASQAGAAAGQGAPAPAPAS
  QEPLPIAGPATAPAPRPLGSIQRPNSFLFRSSSQSGSGPSSPDSVLRPRRYPQVPDEKDL
  MTQLRQVLESRLQRPLPEDLAEALASGVILCQLANQLRPRSVPFIHVPSPAVPKLSALKA
  RKNVESFLEACRKMGVPEADLCSPSDLLQGTARGLRTALEAVKRVGGKALPPLWPPSGLG
  GFVVFYVVLMLLLYVTYTRLLGS
• Function: Accessory protein that regulates signaling by multiple TLRs, acting as a broad-spanning regulator of the innate immune response. In macrophages, binds LPS and promotes proper docking of LPS in lipid raft membrane. May be required for lipid raft maintenance.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammation	DISJUQ5T	Limited	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4) decreases the response to substance of Camptothecin.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[2]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[4]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[6]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Leucine-rich repeat and calponin homology domain-containing protein 4 (LRCH4).	[8]

References

• [1] Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.J Biol Chem. 2019 Feb 8;294(6):1997-2008. doi: 10.1074/jbc.RA118.004300. Epub 2018 Dec 6.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [5] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [8] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [9] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.