Details of Drug Off-Target (DOT)

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

• DOT Name: Leucine-rich repeat protein 1 (LRR1)
• Synonyms: 4-1BB-mediated-signaling molecule; 4-1BBlrr; LRR-repeat protein 1; LRR-1; Peptidylprolyl isomerase-like 5
• Gene Name: LRR1
• Related Disease:
  Autoimmune disease
  Vitiligo
• UniProt ID: LLR1_HUMAN
• PDB ID: 7PLO
• Pfam ID: PF00560 ; PF12799
• Sequence:
  MKLHCEVEVISRHLPALGLRNRGKGVRAVLSLCQQTSRSQPPVRAFLLISTLKDKRGTRY
  ELRENIEQFFTKFVDEGKATVRLKEPPVDICLSKAISSSLKGFLSAMRLAHRGCNVDTPV
  STLTPVKTSEFENFKTKMVITSKKDYPLSKNFPYSLEHLQTSYCGLVRVDMRMLCLKSLR
  KLDLSHNHIKKLPATIGDLIHLQELNLNDNHLESFSVALCHSTLQKSLRSLDLSKNKIKA
  LPVQFCQLQELKNLKLDDNELIQFPCKIGQLINLRFLSAARNKLPFLPSEFRNLSLEYLD
  LFGNTFEQPKVLPVIKLQAPLTLLESSARTILHNRIPYGSHIIPFHLCQDLDTAKICVCG
  RFCLNSFIQGTTTMNLHSVAHTVVLVDNLGGTEAPIISYFCSLGCYVNSSDMLK
• Function: Substrate recognition subunit of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase. May negatively regulate the 4-1BB-mediated signaling cascades which result in the activation of NK-kappaB and JNK1.
• Tissue Specificity: Ubiquitous. Maximal expression was seen in the heart and skeletal muscle and minimal expression seen in the kidney.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Vitiligo	DISR05SL	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Leucine-rich repeat protein 1 (LRR1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leucine-rich repeat protein 1 (LRR1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[5]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[6]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[8]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Leucine-rich repeat protein 1 (LRR1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine-rich repeat protein 1 (LRR1).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Leucine-rich repeat protein 1 (LRR1).	[4]

References

• [1] Polymorphisms in NLRP1 gene and susceptibility to autoimmune thyroid disease.Autoimmunity. 2013 May;46(3):215-21. doi: 10.3109/08916934.2013.768617.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [7] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [8] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [9] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.