Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9IHOGZ)

• DOT Name: Discoidin domain-containing receptor 2 (DDR2)
• Synonyms: Discoidin domain receptor 2; EC 2.7.10.1; CD167 antigen-like family member B; Discoidin domain-containing receptor tyrosine kinase 2; Neurotrophic tyrosine kinase, receptor-related 3; Receptor protein-tyrosine kinase TKT; Tyrosine-protein kinase TYRO10; CD antigen CD167b
• Gene Name: DDR2
• Related Disease:
  Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome
  Warburg-cinotti syndrome
• UniProt ID: DDR2_HUMAN
• PDB ID: 2WUH; 2Z4F; 6FER; 7AZB
• EC Number: 2.7.10.1
• Pfam ID: PF21114 ; PF00754 ; PF07714
• Sequence:
  MILIPRMLLVLFLLLPILSSAKAQVNPAICRYPLGMSGGQIPDEDITASSQWSESTAAKY
  GRLDSEEGDGAWCPEIPVEPDDLKEFLQIDLHTLHFITLVGTQGRHAGGHGIEFAPMYKI
  NYSRDGTRWISWRNRHGKQVLDGNSNPYDIFLKDLEPPIVARFVRFIPVTDHSMNVCMRV
  ELYGCVWLDGLVSYNAPAGQQFVLPGGSIIYLNDSVYDGAVGYSMTEGLGQLTDGVSGLD
  DFTQTHEYHVWPGYDYVGWRNESATNGYIEIMFEFDRIRNFTTMKVHCNNMFAKGVKIFK
  EVQCYFRSEASEWEPNAISFPLVLDDVNPSARFVTVPLHHRMASAIKCQYHFADTWMMFS
  EITFQSDAAMYNNSEALPTSPMAPTTYDPMLKVDDSNTRILIGCLVAIIFILLAIIVIIL
  WRQFWQKMLEKASRRMLDDEMTVSLSLPSDSSMFNNNRSSSPSEQGSNSTYDRIFPLRPD
  YQEPSRLIRKLPEFAPGEEESGCSGVVKPVQPSGPEGVPHYAEADIVNLQGVTGGNTYSV
  PAVTMDLLSGKDVAVEEFPRKLLTFKEKLGEGQFGEVHLCEVEGMEKFKDKDFALDVSAN
  QPVLVAVKMLRADANKNARNDFLKEIKIMSRLKDPNIIHLLAVCITDDPLCMITEYMENG
  DLNQFLSRHEPPNSSSSDVRTVSYTNLKFMATQIASGMKYLSSLNFVHRDLATRNCLVGK
  NYTIKIADFGMSRNLYSGDYYRIQGRAVLPIRWMSWESILLGKFTTASDVWAFGVTLWET
  FTFCQEQPYSQLSDEQVIENTGEFFRDQGRQTYLPQPAICPDSVYKLMLSCWRRDTKNRP
  SFQEIHLLLLQQGDE
• Function: Tyrosine kinase involved in the regulation of tissues remodeling. It functions as a cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing.
• Tissue Specificity: Detected in osteocytes, osteoblastic cells in subchondral bone, bone lining cells, tibia and cartilage (at protein level). Detected at high levels in heart and lung, and at low levels in brain, placenta, liver, skeletal muscle, pancreas, and kidney.
• Reactome Pathway: Non-integrin membrane-ECM interactions (R-HSA-3000171)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome	DISEO1T2	Definitive	Autosomal recessive	[1]
Warburg-cinotti syndrome	DISIBRPU	Moderate	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Discoidin domain-containing receptor 2 (DDR2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[11]
Lithium	DMZ3OU6	Phase 2	Lithium decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[15]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Discoidin domain-containing receptor 2 (DDR2).	[16]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Discoidin domain-containing receptor 2 (DDR2).	[18]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Discoidin domain-containing receptor 2 (DDR2).	[9]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Discoidin domain-containing receptor 2 (DDR2).	[19]

References

• [1] 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.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [9] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells. Anticancer Res. 2015 Feb;35(2):767-74.
• [12] A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder. BMC Syst Biol. 2010 Nov 19;4:158. doi: 10.1186/1752-0509-4-158.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] 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.
• [19] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.