Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0NEJU)

• DOT Name: Lysyl oxidase homolog 1 (LOXL1)
• Synonyms: EC 1.4.3.13; Lysyl oxidase-like protein 1; LOL
• Gene Name: LOXL1
• Related Disease:
  Aortic aneurysm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Bronchopulmonary dysplasia
  Cardiac disease
  Cardiovascular disease
  Cataract
  Central retinal vein occlusion
  Cerebrovascular disease
  Endometriosis
  Liver cirrhosis
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Stroke
  Trichohepatoenteric syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vascular disease
  Advanced cancer
  Gastric cancer
  Pulmonary emphysema
  Pulmonary fibrosis
  Stomach cancer
  Primary congenital glaucoma
  Age-related macular degeneration
  Breast neoplasm
  Metastatic malignant neoplasm
  Minimally invasive lung adenocarcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: LOXL1_HUMAN
• EC Number: 1.4.3.13
• Pfam ID: PF01186
• Sequence:
  MALARGSRQLGALVWGACLCVLVHGQQAQPGQGSDPARWRQLIQWENNGQVYSLLNSGSE
  YVPAGPQRSESSSRVLLAGAPQAQQRRSHGSPRRRQAPSLPLPGRVGSDTVRGQARHPFG
  FGQVPDNWREVAVGDSTGMARARTSVSQQRHGGSASSVSASAFASTYRQQPSYPQQFPYP
  QAPFVSQYENYDPASRTYDQGFVYYRPAGGGVGAGAAAVASAGVIYPYQPRARYEEYGGG
  EELPEYPPQGFYPAPERPYVPPPPPPPDGLDRRYSHSLYSEGTPGFEQAYPDPGPEAAQA
  HGGDPRLGWYPPYANPPPEAYGPPRALEPPYLPVRSSDTPPPGGERNGAQQGRLSVGSVY
  RPNQNGRGLPDLVPDPNYVQASTYVQRAHLYSLRCAAEEKCLASTAYAPEATDYDVRVLL
  RFPQRVKNQGTADFLPNRPRHTWEWHSCHQHYHSMDEFSHYDLLDAATGKKVAEGHKASF
  CLEDSTCDFGNLKRYACTSHTQGLSPGCYDTYNADIDCQWIDITDVQPGNYILKVHVNPK
  YIVLESDFTNNVVRCNIHYTGRYVSATNCKIVQS
• Function: Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers. Essential for the elastic fiber homeostasis and for their maintenance at adult age.
• Tissue Specificity: Expressed in ocular tissues including the iris, ciliary body, lens and optic nerve. Not detected in the retina.
• Reactome Pathway:
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Elastic fibre formation (R-HSA-1566948)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic aneurysm	DISQ5KRA	Strong	Altered Expression	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Cataract	DISUD7SL	Strong	Genetic Variation	[7]
Central retinal vein occlusion	DIS5ICKE	Strong	Genetic Variation	[7]
Cerebrovascular disease	DISAB237	Strong	Genetic Variation	[6]
Endometriosis	DISX1AG8	Strong	Altered Expression	[8]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[9]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Stroke	DISX6UHX	Strong	Genetic Variation	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Vascular disease	DISVS67S	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[10]
Gastric cancer	DISXGOUK	moderate	Biomarker	[12]
Pulmonary emphysema	DIS5M7HZ	moderate	Biomarker	[13]
Pulmonary fibrosis	DISQKVLA	moderate	Biomarker	[14]
Stomach cancer	DISKIJSX	moderate	Biomarker	[12]
Primary congenital glaucoma	DISY7HN4	Disputed	Genetic Variation	[15]
Age-related macular degeneration	DIS0XS2C	Limited	Genetic Variation	[16]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[18]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Biomarker	[17]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[19]

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 Lysyl oxidase homolog 1 (LOXL1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysyl oxidase homolog 1 (LOXL1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lysyl oxidase homolog 1 (LOXL1).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Lysyl oxidase homolog 1 (LOXL1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysyl oxidase homolog 1 (LOXL1).	[25]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Lysyl oxidase homolog 1 (LOXL1).	[26]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysyl oxidase homolog 1 (LOXL1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[32]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[30]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Lysyl oxidase homolog 1 (LOXL1).	[30]

References

• [1] LncRNA LOXL1-AS is up-regulated in thoracic aortic aneurysm and regulated proliferation and apoptosis of aortic smooth muscle cells.Biosci Rep. 2019 Sep 13;39(9):BSR20191649. doi: 10.1042/BSR20191649. Print 2019 Sep 30.
• [2] LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer.Cancer Res. 2007 May 1;67(9):4123-9. doi: 10.1158/0008-5472.CAN-07-0012. Epub 2007 Apr 24.
• [3] Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.J Mol Med (Berl). 2012 Jul;90(7):803-15. doi: 10.1007/s00109-011-0855-y. Epub 2012 Jan 10.
• [4] Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs.Am J Respir Crit Care Med. 2009 Dec 15;180(12):1239-52. doi: 10.1164/rccm.200902-0215OC. Epub 2009 Sep 24.
• [5] Role of the lysyl oxidase enzyme family in cardiac function and disease.Cardiovasc Res. 2019 Nov 1;115(13):1820-1837. doi: 10.1093/cvr/cvz176.
• [6] LOXL1 gene sequence variants and vascular disease in exfoliation syndrome and exfoliative glaucoma.J Glaucoma. 2011 Mar;20(3):143-7. doi: 10.1097/IJG.0b013e3181d9d8dd.
• [7] Lack of association of LOXL1 gene variants in Japanese patients with central retinal vein occlusion without clinically detectable pseudoexfoliation material deposits.Acta Ophthalmol. 2015 May;93(3):e214-7. doi: 10.1111/aos.12534. Epub 2014 Aug 12.
• [8] Deregulation of LOXL1 and HTRA1 gene expression in endometriosis.Reprod Sci. 2010 Nov;17(11):1016-23. doi: 10.1177/1933719110377662.
• [9] Inhibition of lysyl oxidase-like 1 (LOXL1) expression arrests liver fibrosis progression in cirrhosis by reducing elastin crosslinking.Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt A):1129-1137. doi: 10.1016/j.bbadis.2018.01.019. Epub 2018 Jan 31.
• [10] LOXL1 Is Regulated by Integrin 11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity.Cancers (Basel). 2019 May 22;11(5):705. doi: 10.3390/cancers11050705.
• [11] An investigation into LOXL1 variants in black South African individuals with exfoliation syndrome.Arch Ophthalmol. 2011 Feb;129(2):206-10. doi: 10.1001/archophthalmol.2010.349.
• [12] Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer.Digestion. 2018;98(4):238-248. doi: 10.1159/000489558. Epub 2018 Jul 25.
• [13] The copper dependent-lysyl oxidases contribute to the pathogenesis of pulmonary emphysema in chronic obstructive pulmonary disease patients.J Trace Elem Med Biol. 2017 Dec;44:247-255. doi: 10.1016/j.jtemb.2017.08.011. Epub 2017 Sep 1.
• [14] Lysyl Oxidase-Like 1 Protein Deficiency Protects Mice from Adenoviral Transforming Growth Factor-1-induced Pulmonary Fibrosis.Am J Respir Cell Mol Biol. 2018 Apr;58(4):461-470. doi: 10.1165/rcmb.2017-0252OC.
• [15] The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure.J Ocul Pharmacol Ther. 2014 Mar-Apr;30(2-3):170-80. doi: 10.1089/jop.2013.0184. Epub 2014 Feb 12.
• [16] Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration.Am J Ophthalmol. 2011 Mar;151(3):550-6.e1. doi: 10.1016/j.ajo.2010.08.048. Epub 2011 Jan 13.
• [17] Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas.Lab Invest. 1998 Feb;78(2):143-51.
• [18] ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis.Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6836-6841. doi: 10.1073/pnas.1817473116. Epub 2019 Mar 19.
• [19] Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.BMC Med Genomics. 2015 Dec 21;8:83. doi: 10.1186/s12920-015-0160-7.
• [20] 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.
• [21] 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.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [25] 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.
• [26] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [27] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [28] 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.
• [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] BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.
• [31] 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.
• [32] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.