discoidin domain receptor tyrosine kinase 2 | Type XVI RTKs: DDR (collagen receptor) family | IUPHAR/BPS Guide to PHARMACOLOGY

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discoidin domain receptor tyrosine kinase 2

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

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 1 855 1q12-q23 DDR2 discoidin domain receptor tyrosine kinase 2
Mouse 1 854 1 H1-H5 Ddr2 discoidin domain receptor family, member 2
Rat - 854 13q24 Ddr2 discoidin domain receptor tyrosine kinase 2
Previous and Unofficial Names
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
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
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
DDR1/2 inhibitor 5n Hs Inhibition 8.1 pKd 12
pKd 8.1 (Kd 8x10-9 M) [12]
nilotinib Hs Inhibition 9.3 pIC50 7
pIC50 9.3 (IC50 5x10-10 M) [7]
sitravatinib Hs Inhibition 9.3 pIC50 11
pIC50 9.3 (IC50 5x10-10 M) [11]
Description: In a biochemical enzyme activity assay.
sorafenib Hs Inhibition 8.0 pIC50 8
pIC50 8.0 (IC50 1x10-8 M) [8]
RIPK3 inhibitor 18 Hs Inhibition 8.0 pIC50 6
pIC50 8.0 (IC50 1.1x10-8 M) [6]
DDR1/2 inhibitor 5n Hs Inhibition 7.7 pIC50 12
pIC50 7.7 (IC50 2.04x10-8 M) [12]
compound 1 [PMID: 31477924] Hs Inhibition 6.6 pIC50 14
pIC50 6.6 (IC50 2.34x10-7 M) [14]
Description: In vitro inhibitory activity in an enzymatic kinase assay.
DDR-IN-1 Hs Inhibition 6.4 pIC50 7
pIC50 6.4 (IC50 4.13x10-7 M) [7]
Description: In a Lanthascreen enzyme assay
imatinib Hs Inhibition 6.2 pIC50 7
pIC50 6.2 (IC50 6.75x10-7 M) [7]
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: 4,13

Key to terms and symbols Click column headers to sort
Target used in screen: DDR2
Ligand Sp. Type Action Value Parameter
dasatinib Hs Inhibitor Inhibition 8.5 pKd
foretinib Hs Inhibitor Inhibition 8.4 pKd
sorafenib Hs Inhibitor Inhibition 8.2 pKd
AST-487 Hs Inhibitor Inhibition 8.0 pKd
PD-173955 Hs Inhibitor Inhibition 7.9 pKd
imatinib Hs Inhibitor Inhibition 7.8 pKd
masitinib Hs Inhibitor Inhibition 7.6 pKd
doramapimod Hs Inhibitor Inhibition 7.5 pKd
nilotinib Hs Inhibitor Inhibition 7.5 pKd
staurosporine 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
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 Hs Inhibitor Inhibition 0.2
nilotinib Hs Inhibitor Inhibition 1.8
sorafenib Hs Inhibitor Inhibition 3.4
staurosporine Hs Inhibitor Inhibition 3.8 4.0 0.0
imatinib Hs Inhibitor Inhibition 27.1
TWS119 Hs Inhibitor Inhibition 29.3 23.0 4.0
pazopanib Hs Inhibitor Inhibition 36.2
masitinib Hs Inhibitor Inhibition 36.4
PDGF RTK inhibitor Hs Inhibitor Inhibition 54.1 26.0 11.0
PDK1/Akt/Flt dual pathway inhibitor 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
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 Medicinal Chemistry Letters, 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. 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. 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 09/09/2019. Accessed on 17/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1844.