Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYW1SH8)

• DOT Name: Epithelial discoidin domain-containing receptor 1 (DDR1)
• Synonyms: Epithelial discoidin domain receptor 1; EC 2.7.10.1; CD167 antigen-like family member A; Cell adhesion kinase; Discoidin receptor tyrosine kinase; HGK2; Mammary carcinoma kinase 10; MCK-10; Protein-tyrosine kinase 3A; Protein-tyrosine kinase RTK-6; TRK E; Tyrosine kinase DDR; Tyrosine-protein kinase CAK; CD antigen CD167a
• Gene Name: DDR1
• UniProt ID: DDR1_HUMAN
• PDB ID: 3ZOS ; 4AG4 ; 4BKJ ; 4CKR ; 5BVK ; 5BVN ; 5BVO ; 5BVW ; 5FDP ; 5FDX ; 5SAU ; 5SAV ; 5SAW ; 5SAX ; 5SAY ; 5SAZ ; 5SB0 ; 5SB1 ; 5SB2 ; 6BRJ ; 6BSD ; 6FEW ; 6FEX ; 6FIL ; 6FIN ; 6FIO ; 6FIQ ; 6GWR ; 6HP9 ; 6Y23 ; 7BCM ; 7BE6 ; 7FEH ; 8PE9
• EC Number: 2.7.10.1
• Pfam ID: PF21114 ; PF00754 ; PF07714
• Sequence:
  MGPEALSSLLLLLLVASGDADMKGHFDPAKCRYALGMQDRTIPDSDISASSSWSDSTAAR
  HSRLESSDGDGAWCPAGSVFPKEEEYLQVDLQRLHLVALVGTQGRHAGGLGKEFSRSYRL
  RYSRDGRRWMGWKDRWGQEVISGNEDPEGVVLKDLGPPMVARLVRFYPRADRVMSVCLRV
  ELYGCLWRDGLLSYTAPVGQTMYLSEAVYLNDSTYDGHTVGGLQYGGLGQLADGVVGLDD
  FRKSQELRVWPGYDYVGWSNHSFSSGYVEMEFEFDRLRAFQAMQVHCNNMHTLGARLPGG
  VECRFRRGPAMAWEGEPMRHNLGGNLGDPRARAVSVPLGGRVARFLQCRFLFAGPWLLFS
  EISFISDVVNNSSPALGGTFPPAPWWPPGPPPTNFSSLELEPRGQQPVAKAEGSPTAILI
  GCLVAIILLLLLIIALMLWRLHWRRLLSKAERRVLEEELTVHLSVPGDTILINNRPGPRE
  PPPYQEPRPRGNPPHSAPCVPNGSALLLSNPAYRLLLATYARPPRGPGPPTPAWAKPTNT
  QAYSGDYMEPEKPGAPLLPPPPQNSVPHYAEADIVTLQGVTGGNTYAVPALPPGAVGDGP
  PRVDFPRSRLRFKEKLGEGQFGEVHLCEVDSPQDLVSLDFPLNVRKGHPLLVAVKILRPD
  ATKNARNDFLKEVKIMSRLKDPNIIRLLGVCVQDDPLCMITDYMENGDLNQFLSAHQLED
  KAAEGAPGDGQAAQGPTISYPMLLHVAAQIASGMRYLATLNFVHRDLATRNCLVGENFTI
  KIADFGMSRNLYAGDYYRVQGRAVLPIRWMAWECILMGKFTTASDVWAFGVTLWEVLMLC
  RAQPFGQLTDEQVIENAGEFFRDQGRQVYLSRPPACPQGLYELMLRCWSRESEQRPPFSQ
  LHRFLAEDALNTV
• Function: Tyrosine kinase that functions as a cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing. Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11.
• Tissue Specificity: Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin.
• Reactome Pathway: Non-integrin membrane-ECM interactions (R-HSA-3000171)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Epithelial discoidin domain-containing receptor 1 (DDR1) affects the response to substance of Cisplatin.	[18]
Mitomycin	DMH0ZJE	Approved	Epithelial discoidin domain-containing receptor 1 (DDR1) affects the response to substance of Mitomycin.	[18]

16 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 Epithelial discoidin domain-containing receptor 1 (DDR1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[6]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[10]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Epithelial discoidin domain-containing receptor 1 (DDR1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Epithelial discoidin domain-containing receptor 1 (DDR1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Epithelial discoidin domain-containing receptor 1 (DDR1).	[15]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] 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.
• [5] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [6] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] 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.
• [9] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [12] 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.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.