protein tyrosine kinase 2 | Fak family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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protein tyrosine kinase 2

  Target has curated data in GtoImmuPdb

Target id: 2180

Nomenclature: protein tyrosine kinase 2

Abbreviated Name: FAK

Family: Fak 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 - 1074 8q24.3 PTK2 protein tyrosine kinase 2
Mouse - 1052 15 D3 Ptk2 PTK2 protein tyrosine kinase 2
Rat - 1055 7 q34 Ptk2 protein tyrosine kinase 2
Previous and Unofficial Names
FADK | FADK 1 | FAK1 | focal adhesion kinase | FRNK | p125FAK
Database Links
BRENDA
CATH/Gene3D
ChEMBL 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:  Structure of Focal Adhesion Kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.
PDB Id:  4I4E
Resolution:  1.55Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  Structure of Focal Adhesion Kinase catalytic domain in complex with an allosteric binding pyrazolobenzothiazine compound.
PDB Id:  4I4F
Ligand:  compound 30 [PMID: 23414845]
Resolution:  1.75Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure Analysis of Focal Adhesion Kinase with a Methanesulfonamide Diaminopyrimidine Inhibitor
PDB Id:  3BZ3
Ligand:  PF-562271
Resolution:  2.2Å
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 Value Parameter Reference
VS-4718 Hs Inhibition 8.8 pIC50 12
pIC50 8.8 (IC50 1.5x10-9 M) [12]
PF-562271 Hs Inhibition 8.8 pIC50 9
pIC50 8.8 (IC50 1.5x10-9 M) [9]
CEP-37440 Hs Inhibition 8.7 pIC50 7
pIC50 8.7 (IC50 2x10-9 M) [7]
NVP-TAE 226 Hs Inhibition 8.3 pIC50 6,10
pIC50 8.3 (IC50 5.5x10-9 M) [6,10]
conteltinib Hs Inhibition >7.7 pIC50 15
pIC50 >7.7 (IC50 <2x10-8 M) [15]
Description: In a time-resolved fluorescence (TRF) assay using recombinant GST-tagged FAK.
ENMD-2076 Hs Inhibition 7.3 pIC50 8
pIC50 7.3 (IC50 5.5x10-8 M) [8]
compound 30 [PMID: 23414845] Hs Inhibition 6.2 pIC50 13
pIC50 6.2 (IC50 6.4x10-7 M) [13]
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: 3,14

Key to terms and symbols Click column headers to sort
Target used in screen: FAK
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Hs Inhibitor Inhibition 9.0 pKd
fedratinib Hs Inhibitor Inhibition 7.4 pKd
staurosporine Hs Inhibitor Inhibition 7.2 pKd
BI-2536 Hs Inhibitor Inhibition 6.8 pKd
foretinib Hs Inhibitor Inhibition 6.7 pKd
GSK-1838705A Hs Inhibitor Inhibition 6.7 pKd
tamatinib Hs Inhibitor Inhibition 6.6 pKd
crizotinib Hs Inhibitor Inhibition 6.5 pKd
sunitinib Hs Inhibitor Inhibition 6.4 pKd
bosutinib Hs Inhibitor Inhibition 6.2 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: 1,4

Key to terms and symbols Click column headers to sort
Target used in screen: FAK/FAK(PTK2)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 4.3 5.5 -0.5
SB 218078 Hs Inhibitor Inhibition 23.5 105.0 67.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 25.3 20.0 -1.0
SU11652 Hs Inhibitor Inhibition 25.8 15.0 4.0
sunitinib Hs Inhibitor Inhibition 27.0
SU6656 Hs Inhibitor Inhibition 33.1 21.0 8.0
indirubin derivative E804 Hs Inhibitor Inhibition 35.0 16.0 1.0
JAK inhibitor I Hs Inhibitor Inhibition 35.3 51.0 9.0
Syk inhibitor II Hs Inhibitor Inhibition 44.0 64.0 7.0
isogranulatimide Hs Inhibitor Inhibition 56.9 57.0 25.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
FAK and Pyk2 are phosphorylated downstream of the T cell antigen receptor (TCR) to bring about receptor-specific T cell development and activation [2]. Hyperactivated FAK activity that has been detected in the tumour microenvironment of various solid tumour types is reported to be immunosuppressive [5,11]. Targeted FAK inhibition potentiates the efficacy of checkpoint immunotherapy in pancreatic cancers [5].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS

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. Chapman NM, Houtman JC. (2014) Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol. Res., 59 (1-3): 23-34. [PMID:24816556]

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 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]

5. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT et al.. (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med., 22 (8): 851-60. [PMID:27376576]

6. Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. (2007) Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol. Cancer Ther., 6 (4): 1357-67. [PMID:17431114]

7. Ott GR, Cheng M, Learn KS, Wagner J, Gingrich DE, Lisko JG, Curry M, Mesaros EF, Ghose AK, Quail MR et al.. (2016) Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK). J. Med. Chem., 59 (16): 7478-96. [PMID:27527804]

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

9. Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J et al.. (2008) Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 68 (6): 1935-44. [PMID:18339875]

10. Shi Q, Hjelmeland AB, Keir ST, Song L, Wickman S, Jackson D, Ohmori O, Bigner DD, Friedman HS, Rich JN. (2007) A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol. Carcinog., 46 (6): 488-96. [PMID:17219439]

11. Sulzmaier FJ, Jean C, Schlaepfer DD. (2014) FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer, 14 (9): 598-610. [PMID:25098269]

12. Tanjoni I, Walsh C, Uryu S, Tomar A, Nam JO, Mielgo A, Lim ST, Liang C, Koenig M, Sun C et al.. (2010) PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol. Ther., 9 (10): 764-77. [PMID:20234191]

13. Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y et al.. (2013) Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg. Med. Chem. Lett., 23 (6): 1779-85. [PMID:23414845]

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. Xiao D, Cheng L, Liu X, Hu Y, Xu X, Liu Z, Zhang L, Wu W, Wang S, Shen Y et al.. (2012) 2,4-DIAMINO-6,7-DIHYDRO-5H-PYRROLO[2,3]PYRIMIDINE DERIVATIVES AS FAK/Pyk2 INHIBITORS. Patent number: WO2012092880. Assignee: Centaurus Biopharma Co., Ltd.. Priority date: 07/01/2011. Publication date: 12/07/2012.

How to cite this page

Fak family: protein tyrosine kinase 2. Last modified on 05/12/2018. Accessed on 23/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2180.