SRC proto-oncogene, non-receptor tyrosine kinase | Src family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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SRC proto-oncogene, non-receptor tyrosine kinase

Target id: 2206

Nomenclature: SRC proto-oncogene, non-receptor tyrosine kinase

Abbreviated Name: Src

Family: Src family

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

   GtoImmuPdb view: ON :     SRC proto-oncogene, non-receptor tyrosine kinase has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 536 20q12-q13 SRC SRC proto-oncogene, non-receptor tyrosine kinase
Mouse - 535 2 H1 Src Rous sarcoma oncogene
Rat - 542 3 q42 Src SRC proto-oncogene, non-receptor tyrosine kinase
Previous and Unofficial Names
ASV | c-Src | p60-Src | SRC1 | SRC proto-oncogene
Database Links
BRENDA
CATH/Gene3D
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Three-dimensional crystal structure of the tyrosine kinase c-Src.
PDB Id:  1FMK
Resolution:  1.5Å
Species:  Human
References:  28
Image of receptor 3D structure from RCSB PDB
Description:  Structure of unphosphorylated c-Src in complex with an inhibitor (imatinib)
PDB Id:  1Y57
Ligand:  imatinib
Resolution:  1.91Å
Species:  Human
References:  9
Enzyme Reaction
EC Number: 2.7.10.2

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 Affinity Units Reference
PD166285 Hs Inhibition 8.1 pKi 22
pKi 8.1 (Ki 8.4x10-9 M) [22]
GSK-3 inhibitor XIII Hs Inhibition 7.1 pKi 5
pKi 7.1 (Ki 8.1x10-8 M) [5]
acalabrutinib Hs Inhibition <6.0 pEC50 4
pEC50 <6.0 (EC50 >1x10-6 M) [4]
eCF506 Hs Inhibition >9.3 pIC50 11
pIC50 >9.3 (IC50 <5x10-10 M) [11]
dasatinib Hs Inhibition 9.1 pIC50 21
pIC50 9.1 (IC50 8x10-10 M) [21]
bosutinib Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
compound 2 [PMID: 15546730] Hs Inhibition >9.0 pIC50 8
pIC50 >9.0 (IC50 <1x10-9 M) [8]
dorsomorphin Hs Inhibition 8.7 pIC50 19
pIC50 8.7 (IC50 2x10-9 M) [19]
Description: Assayed using AMPK heterotrimeric complex containing α2, β1, γ1 subunits
saracatinib Hs Inhibition 8.6 pIC50 14
pIC50 8.6 (IC50 2.7x10-9 M) [14]
WH-4-023 Hs Inhibition 8.2 pIC50 20
pIC50 8.2 (IC50 6x10-9 M) [20]
CCT241161 Hs Inhibition 8.0 pIC50 13
pIC50 8.0 (IC50 1x10-8 M) [13]
PP121 Hs Inhibition 7.8 pIC50 2
pIC50 7.8 (IC50 1.4x10-8 M) [2]
ibrutinib Hs Inhibition 7.7 pIC50 7
pIC50 7.7 (IC50 1.9x10-8 M) [7]
ENMD-2076 Hs Inhibition 7.7 pIC50 23
pIC50 7.7 (IC50 2x10-8 M) [23]
CCT196969 Hs Inhibition 7.5 pIC50 13
pIC50 7.5 (IC50 3x10-8 M) [13]
compound 8h [PMID: 22765894] Hs Inhibition 7.5 pIC50 16
pIC50 7.5 (IC50 3.3x10-8 M) [16]
SU6656 Hs Inhibition 7.1 pIC50 17
pIC50 7.1 (IC50 7.3x10-8 M) [17]
NG-25 Hs Inhibition 6.9 pIC50 25
pIC50 6.9 (IC50 1.13x10-7 M) [25]
balamapimod Hs Inhibition 6.6 pIC50 6
pIC50 6.6 (IC50 2.81x10-7 M) [6]
Description: Measuring inhibition substrate phosphorylation by p60c-src tyrosine kinase in an ELISA, using an anti-phosphotyrosine detection antibody.
compound 36 [PMID: 21958547] Hs Inhibition 6.5 pIC50 15
pIC50 6.5 (IC50 2.98x10-7 M) [15]
Syk inhibitor III Hs Inhibition 4.6 pIC50 26
pIC50 4.6 (IC50 2.73x10-5 M) [26]
KX2-391 Hs Inhibition 4.3 pIC50 24
pIC50 4.3 (IC50 4.6x10-5 M) [24]
Description: Low affinity is expected because the peptide substrate binding site is not well formed when Src is isolated.
KX2-361 Hs Inhibition - - 24
[24]
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: 10,27

Key to terms and symbols Click column headers to sort
Target used in screen: SRC
Ligand Sp. Type Action Affinity Units
dasatinib Hs Inhibitor Inhibition 9.7 pKd
PD-173955 Hs Inhibitor Inhibition 9.1 pKd
bosutinib Hs Inhibitor Inhibition 9.0 pKd
tamatinib Hs Inhibitor Inhibition 8.1 pKd
foretinib Hs Inhibitor Inhibition 7.7 pKd
vandetanib Hs Inhibitor Inhibition 7.2 pKd
fedratinib Hs Inhibitor Inhibition 7.1 pKd
cediranib Hs Inhibitor Inhibition 7.1 pKd
staurosporine Hs Inhibitor Inhibition 7.1 pKd
tozasertib Hs Inhibitor Inhibition 6.8 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: 1,12

Key to terms and symbols Click column headers to sort
Target used in screen: cSrc/c-SRC
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 1.5 3.5 -1.0
TWS119 Hs Inhibitor Inhibition 2.1 6.0 -3.0
dasatinib Hs Inhibitor Inhibition 3.5
aminopurvalanol A Hs Inhibitor Inhibition 3.7 28.0 2.0
dorsomorphin Hs Inhibitor Inhibition 5.8 75.0 9.0
bosutinib Hs Inhibitor Inhibition 6.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 7.6 2.0 3.0
vandetanib Hs Inhibitor Inhibition 11.0
Lck inhibitor Hs Inhibitor Inhibition 13.4 5.0 -1.0
dovitinib Hs Inhibitor Inhibition 16.0
Displaying the top 10 most potent ligands  View all ligands in screen »

References

Show »

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. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol., 4 (11): 691-9. [PMID:18849971]

3. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C et al.. (2007) Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat. Biotechnol., 25 (9): 1035-44. [PMID:17721511]

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. Bebbington D, Binch H, Charrier JD, Everitt S, Fraysse D, Golec J, Kay D, Knegtel R, Mak C, Mazzei F et al.. (2009) The discovery of the potent aurora inhibitor MK-0457 (VX-680). Bioorg. Med. Chem. Lett., 19 (13): 3586-92. [PMID:19447622]

6. Berger DM, Powell DW, Wu B. (2009) 3-quinolinecarbonitrile protein kinase inhibitors. Patent number: US20090062281A1. Assignee: Wyeth LLC. Priority date: 20/02/2004. Publication date: 05/03/2009.

7. 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]

8. Chen P, Norris D, Das J, Spergel SH, Wityak J, Leith L, Zhao R, Chen BC, Pitt S, Pang S et al.. (2004) Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg. Med. Chem. Lett., 14 (24): 6061-6. [PMID:15546730]

9. Cowan-Jacob SW, Fendrich G, Manley PW, Jahnke W, Fabbro D, Liebetanz J, Meyer T. (2005) The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure, 13 (6): 861-71. [PMID:15939018]

10. 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]

11. 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]

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. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M et al.. (2015) Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell, 27 (1): 85-96. [PMID:25500121]

14. Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, Lambert-van der Brempt C, Morgentin R, Norman RA, Olivier A et al.. (2006) N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem., 49 (22): 6465-88. [PMID:17064066]

15. 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]

16. Kim MH, Tsuhako AL, Co EW, Aftab DT, Bentzien F, Chen J, Cheng W, Engst S, Goon L, Klein RR et al.. (2012) The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 22 (15): 4979-85. [PMID:22765894]

17. Lin J, Shen W, Xue J, Sun J, Zhang X, Zhang C. (2012) Novel oxazolo[4,5-g]quinazolin-2(1H)-ones: dual inhibitors of EGFR and Src protein tyrosine kinases. Eur J Med Chem, 55: 39-48. [PMID:22818848]

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

19. Machrouhi F, Ouhamou N, Laderoute K, Calaoagan J, Bukhtiyarova M, Ehrlich PJ, Klon AE. (2010) The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg. Med. Chem. Lett., 20 (22): 6394-9. [PMID:20932747]

20. Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D et al.. (2006) Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J. Med. Chem., 49 (16): 4981-91. [PMID:16884310]

21. O'Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW et al.. (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res., 65 (11): 4500-5. [PMID:15930265]

22. Panek RL, Lu GH, Klutchko SR, Batley BL, Dahring TK, Hamby JM, Hallak H, Doherty AM, Keiser JA. (1997) In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. J. Pharmacol. Exp. Ther., 283 (3): 1433-44. [PMID:9400019]

23. Pollard JR, Mortimore M. (2009) Discovery and development of aurora kinase inhibitors as anticancer agents. J. Med. Chem., 52 (9): 2629-51. [PMID:19320489]

24. Smolinski MP, Bu Y, Clements J, Gelman IH, Hegab T, Cutler DL, Fang JWS, Fetterly G, Kwan R, Barnett A et al.. (2018) Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361). J. Med. Chem., 61 (11): 4704-4719. [PMID:29617135]

25. 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]

26. Wang WY, Hsieh PW, Wu YC, Wu CC. (2007) Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity. Biochem. Pharmacol., 74 (4): 601-11. [PMID:17601492]

27. 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]

28. Xu W, Harrison SC, Eck MJ. (1997) Three-dimensional structure of the tyrosine kinase c-Src. Nature, 385 (6617): 595-602. [PMID:9024657]

How to cite this page

Src family: SRC proto-oncogene, non-receptor tyrosine kinase. Last modified on 26/06/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2206.