Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ8HZCC)

• DOT Name: Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2)
• Synonyms: EC 2.7.10.1; Neurotrophic tyrosine kinase, receptor-related 2
• Gene Name: ROR2
• Related Disease:
  Autosomal dominant Robinow syndrome 1
  Autosomal recessive Robinow syndrome
  Brachydactyly type B1
• UniProt ID: ROR2_HUMAN
• PDB ID: 3ZZW; 4GT4; 6OSH; 6OSN; 6OSV
• EC Number: 2.7.10.1
• Pfam ID: PF01392 ; PF07679 ; PF00051 ; PF07714
• Sequence:
  MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGY
  FLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRL
  RIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGI
  ACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCD
  ARSRTPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANC
  MRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGG
  GHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILYILVPSIAIPLVIAC
  LFFLVCMCRNKQKASASTPQRRQLMASPSQDMEMPLINQHKQAKLKEISLSAVRFMEELG
  EDRFGKVYKGHLFGPAPGEQTQAVAIKTLKDKAEGPLREEFRHEAMLRARLQHPNVVCLL
  GVVTKDQPLSMIFSYCSHGDLHEFLVMRSPHSDVGSTDDDRTVKSALEPPDFVHLVAQIA
  AGMEYLSSHHVVHKDLATRNVLVYDKLNVKISDLGLFREVYAADYYKLLGNSLLPIRWMA
  PEAIMYGKFSIDSDIWSYGVVLWEVFSYGLQPYCGYSNQDVVEMIRNRQVLPCPDDCPAW
  VYALMIECWNEFPSRRPRFKDIHSRLRAWGNLSNYNSSAQTSGASNTTQTSSLSTSPVSN
  VSNARYVGPKQKAPPFPQPQFIPMKGQIRPMVPPPQLYVPVNGYQPVPAYGAYLPNFYPV
  QIPMQMAPQQVPPQMVPKPSSHHSGSGSTSTGYVTTAPSNTSMADRAALLSEGADDTQNA
  PEDGAQSTVQEAEEEEEGSVPETELLGDCDTLQVDEAQVQLEA
• Function: Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes. It seems to be required for cartilage and growth plate development. Phosphorylates YWHAB, leading to induction of osteogenesis and bone formation. In contrast, has also been shown to have very little tyrosine kinase activity in vitro. May act as a receptor for wnt ligand WNT5A which may result in the inhibition of WNT3A-mediated signaling.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)
  PCP/CE pathway (R-HSA-4086400)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant Robinow syndrome 1	DISLYVHM	Definitive	Autosomal dominant	[1]
Autosomal recessive Robinow syndrome	DISV348H	Definitive	Autosomal recessive	[2]
Brachydactyly type B1	DISDVCP4	Definitive	Autosomal dominant	[3]

1 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 Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[4]

7 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 Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tyrosine-protein kinase transmembrane receptor ROR2 (ROR2).	[11]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Phenotypic and mutational spectrum of ROR2-related Robinow syndrome. Hum Mutat. 2022 Jul;43(7):900-918. doi: 10.1002/humu.24375. Epub 2022 May 10.
• [3] Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Am J Hum Genet. 2000 Oct;67(4):822-31. doi: 10.1086/303084. Epub 2000 Sep 12.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [11] 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.