Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0RCL85)

• DOT Name: Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1)
• Synonyms: Calponin homology domain-containing protein 1; Neuronal protein 81; NP81
• Gene Name: LRCH1
• Related Disease:
  Adenoma
  Carcinoma
  Chondrosarcoma
  Colorectal carcinoma
  Nervous system inflammation
  Osteoarthritis
  Stroke
  Multiple sclerosis
• UniProt ID: LRCH1_HUMAN
• Pfam ID: PF00307 ; PF13855
• Sequence:
  MATPGSEPQPFVPALSVATLHPLHHPHHHHHHHQHHGGTGAPGGAGGGGGGSGGFNLPLN
  RGLERALEEAANSGGLNLSARKLKEFPRTAAPGHDLSDTVQADLSKNRLVEVPMELCHFV
  SLEILNLYHNCIRVIPEAIVNLQMLTYLNLSRNQLSALPACLCGLPLKVLIASNNKLGSL
  PEEIGQLKQLMELDVSCNEITALPQQIGQLKSLRELNVRRNYLKVLPQELVDLSLVKFDF
  SCNKVLVIPICFREMKQLQVLLLENNPLQSPPAQICTKGKVHIFKYLSIQACQIKTADSL
  YLHTMERPHLHQHVEDGKKDSDSGVGSDNGDKRLSATEPSDEDTVSLNVPMSNIMEEEQI
  IKEDSCHRLSPVKGEFHQEFQPEPSLLGDSTNSGEERDQFTDRADGLHSEFMNYKARAED
  CEELLRIEEDVHWQTEGIISSSKDQDMDIAMIEQLREAVDLLQDPNGLSTDITERSVLNL
  YPMGSAEALELQDSALNGQIQLETSPVCEVQSDLTLQSNGSQYSPNEIRENSPAVSPTTN
  STAPFGLKPRSVFLRPQRNLESIDPQFTIRRKMEQMREEKELVEQLRESIEMRLKVSLHE
  DLGAALMDGVVLCHLVNHIRPRSVASIHVPSPAVPKLSMAKCRRNVENFLEACRKLGVPE
  ADLCSPCDILQLDFRHIRKTVDTLLALGEKAPPPTSALRSRDLIGFCLVHILFIVLVYIT
  YHWNALSA
• Function: Acts as a negative regulator of GTPase CDC42 by sequestering CDC42-guanine exchange factor DOCK8. Probably by preventing CDC42 activation, negatively regulates CD4(+) T-cell migration.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[3]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[4]
Stroke	DISX6UHX	Strong	Genetic Variation	[5]
Multiple sclerosis	DISB2WZI	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[16]

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 calponin homology domain-containing protein 1 (LRCH1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Leucine-rich repeat and calponin homology domain-containing protein 1 (LRCH1).	[18]

References

• [1] Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression.Genes Chromosomes Cancer. 2014 Apr;53(4):339-48. doi: 10.1002/gcc.22144. Epub 2014 Jan 29.
• [2] Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling.Arthritis Rheum. 2006 Feb;54(2):524-32. doi: 10.1002/art.21624.
• [3] LRCH1 interferes with DOCK8-Cdc42-induced T cell migration and ameliorates experimental autoimmune encephalomyelitis.J Exp Med. 2017 Jan;214(1):209-226. doi: 10.1084/jem.20160068.
• [4] Genetic association analysis of LRCH1 as an osteoarthritis susceptibility locus.Rheumatology (Oxford). 2007 Feb;46(2):250-2. doi: 10.1093/rheumatology/kel265. Epub 2006 Aug 5.
• [5] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.