discoidin domain receptor tyrosine kinase 1 | Type XVI RTKs: DDR (collagen receptor) family | IUPHAR/BPS Guide to PHARMACOLOGY

Top ▲

discoidin domain receptor tyrosine kinase 1

target has curated data in GtoImmuPdb

Target id: 1843

Nomenclature: discoidin domain receptor tyrosine kinase 1

Abbreviated Name: DDR1

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

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 876 6p21.33 DDR1 discoidin domain receptor tyrosine kinase 1
Mouse 1 911 17 C Ddr1 discoidin domain receptor family, member 1
Rat 1 910 20p12 Ddr1 discoidin domain receptor tyrosine kinase 1
Previous and Unofficial Names
cell adhesion kinase | epithelial discoidin domain receptor 1 | HGK2 | neuroepithelial tyrosine kinase | protein-tyrosine kinase RTK 6 | TRK E | neurotrophic tyrosine kinase receptor type 4 | protein-tyrosine kinase 3 | protein-tyrosine kinase PTK-3 | tyrosine-protein kinase CAK | protein-tyrosine kinase MPK-6 | CD167 | EDDR1 | NEP | NTRK4 | discoidin domain receptor family
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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:  11
Enzyme Reaction
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
merestinib Hs Inhibition 9.0 pKd 14
pKd 9.0 (Kd 9.5x10-10 M) [14]
Description: Binding constant determined by KINOMEScan assay.
compound 6j [PMID: 27219676] Hs Inhibition 8.3 pKd 10
pKd 8.3 (Kd 4.7x10-9 M) [10]
Description: Binding affinity
DDR1/2 inhibitor 5n Hs Inhibition 8.1 pKd 11
pKd 8.1 (Kd 7.9x10-9 M) [11]
compound 7k [PMID: 23521020] Hs Inhibition 8.6 pIC50 4
pIC50 8.6 (IC50 2.29x10-9 M) [4]
compound 4 [PMID: 26191369] Hs Inhibition 8.5 pIC50 9
pIC50 8.5 (IC50 3.3x10-9 M) [9]
compound 6j [PMID: 27219676] Hs Inhibition 8.0 pIC50 10
pIC50 8.0 (IC50 9.4x10-9 M) [10]
Description: Inhibition of kinase activity in a TR-FRET assay
DDR1/2 inhibitor 5n Hs Potentiation 8.0 pIC50 11
pIC50 8.0 (IC50 9.4x10-9 M) [11]
compound 1 [PMID: 31477924] Hs Inhibition 8.0 pIC50 15
pIC50 8.0 (IC50 1x10-8 M) [15]
Description: In vitro inhibitory activity in an enzymatic kinase assay.
RIPK1 inhibitor 22b Hs Inhibition 7.5 pIC50 8
pIC50 7.5 (IC50 3.5x10-8 M) [8]
nilotinib Hs Inhibition 7.4 pIC50 5
pIC50 7.4 (IC50 4.3x10-8 M) [5]
DDR-IN-1 Hs Inhibition 7.0 pIC50 5
pIC50 7.0 (IC50 1.05x10-7 M) [5]
Description: In a Lanthascreen enzyme assay
CHMFL-KIT-64 Hs Inhibition 6.9 pIC50 13
pIC50 6.9 (IC50 1.35x10-7 M) [13]
Description: In a biochemical assay.
imatinib Hs Inhibition 6.5 pIC50 5
pIC50 6.5 (IC50 3.37x10-7 M) [5]
DiscoveRx KINOMEscan® screen
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: 3,12

Key to terms and symbols Click column headers to sort
Target used in screen: DDR1
Ligand Sp. Type Action Value Parameter
foretinib Hs Inhibitor Inhibition 9.7 pKd
dasatinib Hs Inhibitor Inhibition 9.2 pKd
AST-487 Hs Inhibitor Inhibition 9.2 pKd
imatinib Hs Inhibitor Inhibition 9.1 pKd
nilotinib Hs Inhibitor Inhibition 9.0 pKd
sorafenib Hs Inhibitor Inhibition 8.8 pKd
cediranib Hs Inhibitor Inhibition 8.8 pKd
doramapimod Hs Inhibitor Inhibition 8.7 pKd
PD-173955 Hs Inhibitor Inhibition 8.6 pKd
masitinib 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

Show »

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. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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 09/09/2019. Accessed on 18/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1843.