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discoidin domain receptor tyrosine kinase 2

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1844

Nomenclature: discoidin domain receptor tyrosine kinase 2

Abbreviated Name: DDR2

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 1 855 1q23.3 DDR2 discoidin domain receptor tyrosine kinase 2
Mouse 1 854 1 76.84 cM Ddr2 discoidin domain receptor family, member 2
Rat - 854 13q24 Ddr2 discoidin domain receptor tyrosine kinase 2
Previous and Unofficial Names Click here for help
CD167b antigen | neurotrophic tyrosine kinase receptor-related 3 | tyrosine-protein kinase TYRO10 | receptor protein-tyrosine kinase TKT | NTRKR3 | TYRO10 | discoidin domain receptor family
Database Links Click here for help
Alphafold Q16832 (Hs), Q62371 (Mm)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.120.260
ChEMBL Target CHEMBL5122 (Hs)
DrugBank Target Q16832 (Hs)
Ensembl Gene ENSG00000162733 (Hs), ENSMUSG00000026674 (Mm), ENSRNOG00000002881 (Rn)
Entrez Gene 4921 (Hs), 18214 (Mm), 685781 (Rn)
Human Protein Atlas ENSG00000162733 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:4921 (Hs), mmu:18214 (Mm), rno:685781 (Rn)
OMIM 191311 (Hs)
Orphanet ORPHA173530 (Hs)
Pharos Q16832 (Hs)
RefSeq Nucleotide NM_001014796 (Hs), NM_022563 (Mm), NM_031764 (Rn)
RefSeq Protein NP_001014796 (Hs), NP_072075 (Mm), NP_113952 (Rn)
UniProtKB Q16832 (Hs), Q62371 (Mm)
Wikipedia DDR2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF THE DDR2 DISCOIDIN DOMAIN BOUND TO A TRIPLE-HELICAL COLLAGEN PEPTIDE
PDB Id:  2WUH
Resolution:  1.6Å
Species:  Human
References:  3
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
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 13
⤷ pKd 8.1 (Kd 8x10-9 M) [13]
naporafenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pKd 12
⤷ pKd 8.0 (Kd 1x10-8 M) [12]
Description: Binding affinity determined using the KinomeScan® platform.
nilotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.3 pIC50 7
⤷ pIC50 9.3 (IC50 5x10-10 M) [7]
sitravatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.3 pIC50 11
⤷ pIC50 9.3 (IC50 5x10-10 M) [11]
Description: In a biochemical enzyme activity assay.
sorafenib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 8
⤷ pIC50 8.0 (IC50 1x10-8 M) [8]
RIPK3 inhibitor 18 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 6
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [6]
DDR1/2 inhibitor 5n Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 13
⤷ pIC50 7.7 (IC50 2.04x10-8 M) [13]
compound 1 [PMID: 31477924] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.6 pIC50 15
⤷ pIC50 6.6 (IC50 2.34x10-7 M) [15]
Description: In vitro inhibitory activity in an enzymatic kinase assay.
DDR-IN-1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.4 pIC50 7
⤷ pIC50 6.4 (IC50 4.13x10-7 M) [7]
Description: In a Lanthascreen enzyme 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 6.2 pIC50 7
⤷ pIC50 6.2 (IC50 6.75x10-7 M) [7]
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: 4,14
Key to terms and symbols Click column headers to sort
Target used in screen: DDR2
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 8.0 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
imatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,5
Key to terms and symbols Click column headers to sort
Target used in screen: DDR2/DDR2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 0.2
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 1.8
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 3.4
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.8 4.0 0.0
imatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 27.1
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 29.3 23.0 4.0
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 36.2
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 36.4
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 54.1 26.0 11.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 58.7 115.0 92.0
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, atherosclerosis and cancer [2,9]. DDR2 is reported to contribute to osteoarthritis [2]. Small molecule inhibitors of these kinases are being developed and investigated for potential anti-inflammatory activity in associated diseases [10].
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Spondylometaepiphyseal dysplasia, short limb-hand type
Synonyms: Spondyloepimetaphyseal dysplasia - short limb - abnormal calcification [Orphanet: ORPHA93358]
OMIM: 271665
Orphanet: ORPHA93358

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

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

3. Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E. (2009) Crystallographic insight into collagen recognition by discoidin domain receptor 2. Structure, 17 (12): 1573-81. [PMID:20004161]

4. 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]

5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

6. Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ et al.. (2019) Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Med Chem Lett, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00065

7. 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]

8. Kitagawa D, Yokota K, Gouda M, Narumi Y, Ohmoto H, Nishiwaki E, Akita K, Kirii Y. (2013) Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells, 18 (2): 110-22. [PMID:23279183]

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

10. 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]

11. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget, 7 (4): 4093-109. [PMID:26675259]

12. 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]

13. 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]

14. 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]

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 2. Last modified on 07/02/2020. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1844.