Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEUYEW6)

• DOT Name: Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1)
• Synonyms: Neurotrophic tyrosine kinase, receptor-related 1
• Gene Name: ROR1
• Related Disease:
  Hearing loss, autosomal recessive 108
  Hearing loss, autosomal recessive
  Nonsyndromic genetic hearing loss
• UniProt ID: ROR1_HUMAN
• PDB ID: 5Z55; 6BA5; 6BAN; 6TU9; 7TNG
• Pfam ID: PF01392 ; PF07679 ; PF00051 ; PF07714
• Sequence:
  MHRPRRRGTRPPLLALLAALLLAARGAAAQETELSVSAELVPTSSWNISSELNKDSYLTL
  DEPMNNITTSLGQTAELHCKVSGNPPPTIRWFKNDAPVVQEPRRLSFRSTIYGSRLRIRN
  LDTTDTGYFQCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYEEDGFCQPYRGIACAR
  FIGNRTVYMESLHMQGEIENQITAAFTMIGTSSHLSDKCSQFAIPSLCHYAFPYCDETSS
  VPKPRDLCRDECEILENVLCQTEYIFARSNPMILMRLKLPNCEDLPQPESPEAANCIRIG
  IPMADPINKNHKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPELNGGHS
  YCRNPGNQKEAPWCFTLDENFKSDLCDIPACDSKDSKEKNKMEILYILVPSVAIPLAIAL
  LFFFICVCRNNQKSSSAPVQRQPKHVRGQNVEMSMLNAYKPKSKAKELPLSAVRFMEELG
  ECAFGKIYKGHLYLPGMDHAQLVAIKTLKDYNNPQQWTEFQQEASLMAELHHPNIVCLLG
  AVTQEQPVCMLFEYINQGDLHEFLIMRSPHSDVGCSSDEDGTVKSSLDHGDFLHIAIQIA
  AGMEYLSSHFFVHKDLAARNILIGEQLHVKISDLGLSREIYSADYYRVQSKSLLPIRWMP
  PEAIMYGKFSSDSDIWSFGVVLWEIFSFGLQPYYGFSNQEVIEMVRKRQLLPCSEDCPPR
  MYSLMTECWNEIPSRRPRFKDIHVRLRSWEGLSSHTSSTTPSGGNATTQTTSLSASPVSN
  LSNPRYPNYMFPSQGITPQGQIAGFIGPPIPQNQRFIPINGYPIPPGYAAFPAAHYQPTG
  PPRVIQHCPPPKSRSPSSASGSTSTGHVTSLPSSGSNQEANIPLLPHMSIPNHPGGMGIT
  VFGNKSQKPYKIDSKQASLLGDANIHGHTESMISAEL
• Function: Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo. Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling. In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells.
• Tissue Specificity: Expressed strongly in human heart, lung and kidney, but weakly in the CNS. Isoform Short is strongly expressed in fetal and adult CNS and in a variety of human cancers, including those originating from CNS or PNS neuroectoderm.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hearing loss, autosomal recessive 108	DISMSLXN	Moderate	Autosomal recessive	[1]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[2]

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 Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[17]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1).	[22]

References

• [1] ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A. 2016 May 24;113(21):5993-8. doi: 10.1073/pnas.1522512113. Epub 2016 May 9.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] 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.
• [18] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.