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LYN proto-oncogene, Src family tyrosine kinase

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2060

Nomenclature: LYN proto-oncogene, Src family tyrosine kinase

Abbreviated Name: Lyn

Family: Src family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 512 8q12.1 LYN LYN proto-oncogene, Src family tyrosine kinase
Mouse - 512 4 2.05 cM Lyn LYN proto-oncogene, Src family tyrosine kinase
Rat - 512 5q12 Lyn LYN proto-oncogene, Src family tyrosine kinase
Gene and Protein Information Comments
A shorter 491 amino acid isoform has been identified in human, mouse and rat. This shorter isoform is termed isoform B, and in all species is 21 amino acids shorter than the cononical isoform (known as isoform A).
Previous and Unofficial Names Click here for help
Hck-2 | JTK8 | p53Lyn | p56Lyn | v-yes-1 Yamaguchi sarcoma viral related oncogene homolog | LYN proto-oncogene
Database Links Click here for help
Alphafold P07948 (Hs), P25911 (Mm), Q07014 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10
ChEMBL Target CHEMBL3905 (Hs), CHEMBL2258 (Mm), CHEMBL4363 (Rn)
Ensembl Gene ENSG00000254087 (Hs), ENSMUSG00000042228 (Mm), ENSRNOG00000008180 (Rn)
Entrez Gene 4067 (Hs), 17096 (Mm), 81515 (Rn)
Human Protein Atlas ENSG00000254087 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:4067 (Hs), mmu:17096 (Mm), rno:81515 (Rn)
OMIM 165120 (Hs)
Pharos P07948 (Hs)
RefSeq Nucleotide NM_001111097 (Hs), NM_001111098 (Hs), NM_010747 (Mm), NM_002350 (Mm), NM_030857 (Rn), NM_001111098 (Rn)
RefSeq Protein NP_001104567 (Hs), NP_002341 (Hs), NP_034877 (Mm), NP_001104566 (Mm), NP_001104568 (Rn), NP_110484 (Rn)
UniProtKB P07948 (Hs), P25911 (Mm), Q07014 (Rn)
Wikipedia LYN (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Lyn kinase domain.
PDB Id:  3A4O
Resolution:  3.0Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  SH3 domain of the human Lyn tyrosine kinase.
PDB Id:  1W1F
Resolution:  0.0Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

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
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.0 pEC50 4
⤷ pEC50 6.0 (EC50 1x10-6 M) [4]
eCF506 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.1 pIC50 9
⤷ pIC50 9.1 (IC50 8x10-10 M) [9]
compound 23 [PMID: 17600705] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 3
⤷ pIC50 9.0 (IC50 1x10-9 M) [3]
bosutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 17
⤷ pIC50 8.1 (IC50 8x10-9 M) [17]
bafetinib 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 13
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [13]
NG-25 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pIC50 20
⤷ pIC50 7.9 (IC50 1.29x10-8 M) [20]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 2x10-8 M) [6]
pexmetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 2
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [2]
SU6656 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pIC50 8
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [8]
xiliertinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 pIC50 18
⤷ pIC50 6.3 (IC50 5.01x10-7 M) [18]
compound 36 [PMID: 21958547] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.2 pIC50 14
⤷ pIC50 6.2 (IC50 6.24x10-7 M) [14]
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition <6.0 pIC50 6
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [6]
Inhibitor Comments
Note that bosutinib has inhibitory activity at other kinases including HCK, ABL1 and SRC.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tolimidone Small molecule or natural product Hs Activation 7.2 pEC50 19
⤷ pEC50 7.2 (EC50 6.3x10-8 M) [19]
Description: Measuring induced increased the V(max) of Lyn.
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: 7,22
Key to terms and symbols Click column headers to sort
Target used in screen: LYN
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.2 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.7 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.8 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 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: 1,12
Key to terms and symbols Click column headers to sort
Target used in screen: Lyn/LYN
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 0.4
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.2 0.5 0.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 2.1
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.5 0.0 1.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 6.0 4.0 1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 2.0 3.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 9.2
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 10.8
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 11.1 2.0 -1.0
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 12.9 14.0 2.0
Target used in screen: nd/LYN B
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 1.6
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.1
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.7
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 12.7
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 14.7
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 16.7
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 18.7
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 21.4
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 21.9
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
LYN is a Src family tyrosine kinase, expressed predominantly in hematopoietic cells, but also in neural, liver, and adipose tissues. LYN appears to function as a rheostat to modulate B cell signaling, and can be activating or inhibitory in action, depending on the B cell receptor and interacting protein complement present in particular cells [10-11,21].
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  15
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   eosinophil (CL:0000771)
neutrophil (CL:0000775)
References:  15
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
References:  15
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  15
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
monocyte (CL:0000576)
References:  15
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
References:  15
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling

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. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res, 76 (16): 4841-4849. [PMID:27287719]

3. Bamborough P, Angell RM, Bhamra I, Brown D, Bull J, Christopher JA, Cooper AW, Fazal LH, Giordano I, Hind L et al.. (2007) N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics. Bioorg Med Chem Lett, 17 (15): 4363-8. [PMID:17600705]

4. Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. (2014) 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk inhibitors. Patent number: US20140155385 A1. Assignee: Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. Priority date: 19/07/2011. Publication date: 05/06/2014.

5. Bauer F, Schweimer K, Meiselbach H, Hoffmann S, Rösch P, Sticht H. (2005) Structural characterization of Lyn-SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinity. Protein Sci, 14 (10): 2487-98. [PMID:16155203]

6. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 374 (4): 323-32. [PMID:26641137]

7. 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]

8. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

9. Fraser C, Dawson JC, Dowling R, Houston DR, Weiss JT, Munro AF, Muir M, Harrington L, Webster SP, Frame MC et al.. (2016) Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. J Med Chem, 59 (10): 4697-710. [PMID:27115835]

10. Freedman TS, Tan YX, Skrzypczynska KM, Manz BN, Sjaastad FV, Goodridge HS, Lowell CA, Weiss A. (2015) LynA regulates an inflammation-sensitive signaling checkpoint in macrophages. Elife, 4. [PMID:26517880]

11. Gao R, Ma Z, Ma M, Yu J, Chen J, Li Z, Shetty S, Fu J. (2015) Deletion of Src family kinase Lyn aggravates endotoxin-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol, 309 (11): L1376-81. [PMID:26453518]

12. 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]

13. Horio T, Hamasaki T, Inoue T, Wakayama T, Itou S, Naito H, Asaki T, Hayase H, Niwa T. (2007) Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives. Bioorg Med Chem Lett, 17 (10): 2712-7. [PMID:17376680]

14. Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J et al.. (2011) Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis. Bioorg Med Chem Lett, 21 (21): 6258-63. [PMID:21958547]

15. Lowell CA. (2004) Src-family kinases: rheostats of immune cell signaling. Mol Immunol, 41 (6-7): 631-43. [PMID:15220000]

16. Miyano N, Kinoshita T, Nakai R, Kirii Y, Yokota K, Tada T. (2009) Structural basis for the inhibitor recognition of human Lyn kinase domain. Bioorg Med Chem Lett, 19 (23): 6557-60. [PMID:19857964]

17. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M et al.. (2009) Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia, 23 (3): 477-85. [PMID:19039322]

18. Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L et al.. (2017) Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification. Oncotarget, 8 (31): 50832-50844. [PMID:28881608]

19. Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG. (2012) MLR-1023 is a potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo. J Pharmacol Exp Ther, 342 (1): 15-22. [PMID:22473614]

20. Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y et al.. (2015) Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). J Med Chem, 58 (1): 183-96. [PMID:25075558]

21. Toubiana J, Rossi AL, Belaidouni N, Grimaldi D, Pene F, Chafey P, Comba B, Camoin L, Bismuth G, Claessens YE et al.. (2015) Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway. Innate Immun, 21 (7): 685-97. [PMID:26055819]

22. 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]

How to cite this page

Src family: LYN proto-oncogene, Src family tyrosine kinase. Last modified on 26/04/2018. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2060.