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discoidin domain receptor tyrosine kinase 1

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Target id: 1843

Nomenclature: discoidin domain receptor tyrosine kinase 1

Abbreviated Name: DDR1

Family: Type XVI RTKs: DDR (collagen receptor) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 913 6p21.33 DDR1 discoidin domain receptor tyrosine kinase 1
Mouse 1 911 17 18.7 cM Ddr1 discoidin domain receptor family, member 1
Rat 1 910 20p12 Ddr1 discoidin domain receptor tyrosine kinase 1
Previous and Unofficial Names Click here for help
cell adhesion kinase | epithelial discoidin domain receptor 1 | HGK2 | neuroepithelial tyrosine kinase | protein-tyrosine kinase RTK 6 | TRK E | protein-tyrosine kinase 3 | neurotrophic tyrosine kinase receptor type 4 | protein-tyrosine kinase PTK-3 | tyrosine-protein kinase CAK | protein-tyrosine kinase MPK-6 | CD167 | EDDR1 | NEP | NTRK4 | discoidin domain receptor family
Database Links Click here for help
Alphafold Q08345 (Hs), Q03146 (Mm), Q63474 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.120.260
ChEMBL Target CHEMBL5319 (Hs), CHEMBL4523274 (Mm), CHEMBL4295859 (Rn)
Ensembl Gene ENSG00000204580 (Hs), ENSMUSG00000003534 (Mm), ENSRNOG00000057125 (Rn)
Entrez Gene 780 (Hs), 12305 (Mm), 25678 (Rn)
Human Protein Atlas ENSG00000204580 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:780 (Hs), mmu:12305 (Mm), rno:25678 (Rn)
OMIM 600408 (Hs)
Pharos Q08345 (Hs)
RefSeq Nucleotide NM_001202521 (Hs), NM_001198833 (Mm), NM_013137 (Rn)
RefSeq Protein NP_001945 (Hs), NP_001185760 (Mm), NP_031610 (Mm), NP_766550 (Mm), NP_001185762 (Mm), NP_037269 (Rn)
UniProtKB Q08345 (Hs), Q03146 (Mm), Q63474 (Rn)
Wikipedia DDR1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of a DDR1-Fab complex
PDB Id:  4AG4
Resolution:  2.8Å
Species:  Human
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Fragment-based discovery of potent and selective DDR1/2 inhibitors
PDB Id:  5BVN
Ligand:  compound 4 [PMID: 26191369]
Resolution:  2.21Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human DDR1 kinase domain in complex with DDR1-IN-1.
PDB Id:  4CKR
Ligand:  DDR-IN-1
Resolution:  2.2Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the kinase domain of human DDR1 in complex with a potent and selective inhibitor of DDR1 and DDR2.
PDB Id:  6GWR
Ligand:  DDR1/2 inhibitor 5n
Resolution:  2.07Å
Species:  Human
References:  12
Enzyme Reaction Click here for help
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
merestinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.0 pKd 15
⤷ pKd 9.0 (Kd 9.5x10-10 M) [15]
Description: Binding constant determined by KINOMEScan assay.
naporafenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pKd 10
⤷ pKd 8.7 (Kd 1.8x10-9 M) [10]
Description: Binding affinity determined using the KinomeScan® platform.
compound 6j [PMID: 27219676] Small molecule or natural product Primary target of this compound Hs Inhibition 8.3 pKd 11
⤷ pKd 8.3 (Kd 4.7x10-9 M) [11]
Description: Binding affinity
DDR1/2 inhibitor 5n Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.1 pKd 12
⤷ pKd 8.1 (Kd 7.9x10-9 M) [12]
compound 7k [PMID: 23521020] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.6 pIC50 4
⤷ pIC50 8.6 (IC50 2.29x10-9 M) [4]
compound 4 [PMID: 26191369] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.5 pIC50 9
⤷ pIC50 8.5 (IC50 3.3x10-9 M) [9]
compound 6j [PMID: 27219676] Small molecule or natural product Primary target of this compound Hs Inhibition 8.0 pIC50 11
⤷ pIC50 8.0 (IC50 9.4x10-9 M) [11]
Description: Inhibition of kinase activity in a TR-FRET assay
DDR1/2 inhibitor 5n Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 12
⤷ pIC50 8.0 (IC50 9.4x10-9 M) [12]
compound 1 [PMID: 31477924] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 16
⤷ pIC50 8.0 (IC50 1x10-8 M) [16]
Description: In vitro inhibitory activity in an enzymatic kinase assay.
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 8
⤷ pIC50 7.5 (IC50 3.5x10-8 M) [8]
nilotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 5
⤷ pIC50 7.4 (IC50 4.3x10-8 M) [5]
DDR-IN-1 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 pIC50 5
⤷ pIC50 7.0 (IC50 1.05x10-7 M) [5]
Description: In a Lanthascreen enzyme assay
CHMFL-KIT-64 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.9 pIC50 14
⤷ pIC50 6.9 (IC50 1.35x10-7 M) [14]
Description: In a biochemical assay.
imatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 5
⤷ pIC50 6.5 (IC50 3.37x10-7 M) [5]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,13
Key to terms and symbols Click column headers to sort
Target used in screen: DDR1
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.7 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 9.2 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.2 pKd
imatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.1 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 9.0 pKd
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 8.8 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.7 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.6 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The DDR1 and DDR2 receptor tyrosine kinases are new potential targets for anti-inflammatory drug discovery, as they are critical mediators of inflammatory-cytokine secretion whose dysregulation is implicated in the progression of various human inflammatory diseases, including fibrosis, arthritis, and cancer [1,6]. DDR1 appears to promote inflammation in atherosclerosis, lung fibrosis and kidney injury. Small molecule inhibitors of these kinases are being developed and investigated for potential anti-inflammatory activity [1,7].

References

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1. Borza CM, Pozzi A. (2014) Discoidin domain receptors in disease. Matrix Biol, 34: 185-92. [PMID:24361528]

2. Carafoli F, Mayer MC, Shiraishi K, Pecheva MA, Chan LY, Nan R, Leitinger B, Hohenester E. (2012) Structure of the discoidin domain receptor 1 extracellular region bound to an inhibitory Fab fragment reveals features important for signaling. Structure, 20 (4): 688-97. [PMID:22483115]

3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

4. Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y, Zhang Z, Tu Z, Xu Y, Ren X et al.. (2013) Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem, 56 (8): 3281-95. [PMID:23521020]

5. Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J et al.. (2013) Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol, 8 (10): 2145-50. [PMID:23899692]

6. Leitinger B. (2014) Discoidin domain receptor functions in physiological and pathological conditions. Int Rev Cell Mol Biol, 310: 39-87. [PMID:24725424]

7. Li Y, Lu X, Ren X, Ding K. (2015) Small molecule discoidin domain receptor kinase inhibitors and potential medical applications. J Med Chem, 58 (8): 3287-301. [PMID:25569119]

8. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J Med Chem, 61 (24): 11398-11414. [PMID:30480444]

9. Murray CW, Berdini V, Buck IM, Carr ME, Cleasby A, Coyle JE, Curry JE, Day JE, Day PJ, Hearn K et al.. (2015) Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS Med Chem Lett, 6 (7): 798-803. [PMID:26191369]

10. Ramurthy S, Taft BR, Aversa RJ, Barsanti PA, Burger MT, Lou Y, Nishiguchi GA, Rico A, Setti L, Smith A et al.. (2020) Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic. J Med Chem, 63 (5): 2013-2027. [PMID:31059256]

11. Wang Z, Bian H, Bartual SG, Du W, Luo J, Zhao H, Zhang S, Mo C, Zhou Y, Xu Y et al.. (2016) Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. J Med Chem, 59 (12): 5911-6. [PMID:27219676]

12. Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H, Cui S, Xiang Q, Xu T, Xun Q et al.. (2018) Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2. J Med Chem, 61 (17): 7977-7990. [PMID:30075624]

13. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

14. Wu Y, Wang B, Wang J, Qi S, Zou F, Qi Z, Liu F, Liu Q, Chen C, Hu C et al.. (2019) Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors. J Med Chem, 62 (13): 6083-6101. [PMID:31250638]

15. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR et al.. (2013) LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs, 31 (4): 833-44. [PMID:23275061]

16. Zhavoronkov A, Ivanenkov YA, Aliper A, Veselov MS, Aladinskiy VA, Aladinskaya AV, Terentiev VA, Polykovskiy DA, Kuznetsov MD, Asadulaev A et al.. (2019) Deep learning enables rapid identification of potent DDR1 kinase inhibitors. Nat Biotechnol, 37 (9): 1038-1040. [PMID:31477924]

How to cite this page

Type XVI RTKs: DDR (collagen receptor) family: discoidin domain receptor tyrosine kinase 1. Last modified on 25/06/2021. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1843.