Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLLY1QI)

• DOT Name: Lysyl oxidase homolog 3 (LOXL3)
• Synonyms: EC 1.4.3.-; EC 1.4.3.13; Lysyl oxidase-like protein 3
• Gene Name: LOXL3
• Related Disease:
  Advanced cancer
  Breast carcinoma
  Carcinoma
  Cardiac disease
  Cleft palate
  Isolated cleft palate
  Neoplasm
  Pulmonary fibrosis
  Stickler syndrome type 1
  Breast cancer
  Stickler syndrome
  Obsolete autosomal recessive Stickler syndrome
  Melanoma
  Metastatic malignant neoplasm
  Myopia 28, autosomal recessive
  Neuroblastoma
• UniProt ID: LOXL3_HUMAN
• EC Number: 1.4.3.-; 1.4.3.13
• Pfam ID: PF01186 ; PF00530
• Sequence:
  MRPVSVWQWSPWGLLLCLLCSSCLGSPSPSTGPEKKAGSQGLRFRLAGFPRKPYEGRVEI
  QRAGEWGTICDDDFTLQAAHILCRELGFTEATGWTHSAKYGPGTGRIWLDNLSCSGTEQS
  VTECASRGWGNSDCTHDEDAGVICKDQRLPGFSDSNVIEVEHHLQVEEVRIRPAVGWGRR
  PLPVTEGLVEVRLPDGWSQVCDKGWSAHNSHVVCGMLGFPSEKRVNAAFYRLLAQRQQHS
  FGLHGVACVGTEAHLSLCSLEFYRANDTARCPGGGPAVVSCVPGPVYAASSGQKKQQQSK
  PQGEARVRLKGGAHPGEGRVEVLKASTWGTVCDRKWDLHAASVVCRELGFGSAREALSGA
  RMGQGMGAIHLSEVRCSGQELSLWKCPHKNITAEDCSHSQDAGVRCNLPYTGAETRIRLS
  GGRSQHEGRVEVQIGGPGPLRWGLICGDDWGTLEAMVACRQLGLGYANHGLQETWYWDSG
  NITEVVMSGVRCTGTELSLDQCAHHGTHITCKRTGTRFTAGVICSETASDLLLHSALVQE
  TAYIEDRPLHMLYCAAEENCLASSARSANWPYGHRRLLRFSSQIHNLGRADFRPKAGRHS
  WVWHECHGHYHSMDIFTHYDILTPNGTKVAEGHKASFCLEDTECQEDVSKRYECANFGEQ
  GITVGCWDLYRHDIDCQWIDITDVKPGNYILQVVINPNFEVAESDFTNNAMKCNCKYDGH
  RIWVHNCHIGDAFSEEANRRFERYPGQTSNQII
• Function: Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins. Catalyzes the post-translational oxidative deamination of peptidyl lysine residues in precursors of elastin and different types of collagens, a prerequisite in the formation of cross-links between collagens and elastin. Required for somite boundary formation by catalyzing oxidation of fibronectin (FN1), enhancing integrin signaling in myofibers and their adhesion to the myotendinous junction (MTJ). Acts as a regulator of inflammatory response by inhibiting differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acts by interacting with STAT3 in the nucleus and catalyzing both deacetylation and oxidation of lysine residues on STAT3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. Also able to catalyze deacetylation of lysine residues on STAT3 ; [Isoform 1]: Shows protein-lysine 6-oxidase activity toward elastin and different types of collagens, with the highest activity toward collagen type VIII ; [Isoform 2]: Shows protein-lysine 6-oxidase activity toward elastin and different types of collagens, with the highest activity toward collagen type IV.
• Tissue Specificity: Isoform 1: Predominantly detected in the heart, placenta, lung, and small intestine . Isoform 2: Highly detected in the kidney, pancreas, spleen, and thymus, and is absent in lung . In eye, present in all layers of corneas as well as in the limbus and conjunctiva (at protein level) .
• Reactome Pathway:
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Elastic fibre formation (R-HSA-1566948)
• BioCyc Pathway: MetaCyc:ENSG00000115318-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[5]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[7]
Stickler syndrome type 1	DIST5L4S	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[2]
Stickler syndrome	DISQWFHN	Moderate	Autosomal recessive	[9]
Obsolete autosomal recessive Stickler syndrome	DISCSIL9	Supportive	Autosomal recessive	[8]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[11]
Myopia 28, autosomal recessive	DISNJ929	Limited	Unknown	[12]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Lysyl oxidase homolog 3 (LOXL3).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysyl oxidase homolog 3 (LOXL3).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lysyl oxidase homolog 3 (LOXL3).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysyl oxidase homolog 3 (LOXL3).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Lysyl oxidase homolog 3 (LOXL3).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Lysyl oxidase homolog 3 (LOXL3).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Lysyl oxidase homolog 3 (LOXL3).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysyl oxidase homolog 3 (LOXL3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysyl oxidase homolog 3 (LOXL3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lysyl oxidase homolog 3 (LOXL3).	[21]

References

• [1] The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis.J Cell Mol Med. 2019 Mar;23(3):1759-1770. doi: 10.1111/jcmm.14074. Epub 2018 Dec 9.
• [2] 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.
• [3] Lysyl oxidase-like 4 is alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities.Virchows Arch. 2009 Jan;454(1):71-9. doi: 10.1007/s00428-008-0694-6. Epub 2008 Nov 18.
• [4] 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.
• [5] Association between a common missense variant in LOXL3 gene and the risk of non-syndromic cleft palate.Congenit Anom (Kyoto). 2018 Jul;58(4):136-140. doi: 10.1111/cga.12288. Epub 2018 Jun 11.
• [6] Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability.Cell Death Differ. 2018 May;25(5):935-950. doi: 10.1038/s41418-017-0030-2. Epub 2017 Dec 11.
• [7] Identification and Optimization of Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3.J Med Chem. 2019 Nov 14;62(21):9874-9889. doi: 10.1021/acs.jmedchem.9b01283. Epub 2019 Oct 16.
• [8] LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome. Clin Genet. 2019 Feb;95(2):325-328. doi: 10.1111/cge.13465. Epub 2018 Nov 18.
• [9] LOXL3, encoding lysyl oxidase-like 3, is mutated in a family with autosomal recessive Stickler syndrome. Hum Genet. 2015 Apr;134(4):451-3. doi: 10.1007/s00439-015-1531-z. Epub 2015 Feb 7.
• [10] LOXL3 Function Beyond Amino Oxidase and Role in Pathologies, Including Cancer.Int J Mol Sci. 2019 Jul 23;20(14):3587. doi: 10.3390/ijms20143587.
• [11] 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.
• [12] Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia. Mol Vis. 2016 Feb 20;22:161-7. eCollection 2016.
• [13] LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.Cancer Cell. 2017 Sep 11;32(3):310-323.e5. doi: 10.1016/j.ccell.2017.08.002. Epub 2017 Aug 31.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] 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.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [20] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [21] 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.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] 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.