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protein tyrosine kinase 2

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2180

Nomenclature: protein tyrosine kinase 2

Abbreviated Name: FAK

Family: Fak family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1052 8q24.3 PTK2 protein tyrosine kinase 2
Mouse - 1052 15 33.94 cM Ptk2 PTK2 protein tyrosine kinase 2
Rat - 1055 7q34 Ptk2 protein tyrosine kinase 2
Previous and Unofficial Names Click here for help
FADK | FADK 1 | FAK1 | focal adhesion kinase | FRNK | p125FAK
Database Links Click here for help
Alphafold Q05397 (Hs), P34152 (Mm), O35346 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 1.20.80.10
ChEMBL Target CHEMBL2695 (Hs), CHEMBL1075288 (Mm), CHEMBL5773 (Rn)
Ensembl Gene ENSG00000169398 (Hs), ENSMUSG00000022607 (Mm), ENSRNOG00000007916 (Rn)
Entrez Gene 5747 (Hs), 14083 (Mm), 25614 (Rn)
Human Protein Atlas ENSG00000169398 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:5747 (Hs), mmu:14083 (Mm), rno:25614 (Rn)
OMIM 600758 (Hs)
Pharos Q05397 (Hs)
RefSeq Nucleotide NM_001199649 (Hs), NM_007982 (Mm), NM_013081 (Rn)
RefSeq Protein NP_005598 (Hs), NP_032008 (Mm), NP_037213 (Rn)
SynPHARM 83989 (in complex with PF-562271)
UniProtKB Q05397 (Hs), P34152 (Mm), O35346 (Rn)
Wikipedia PTK2 (Hs)
Selected 3D Structures Click here for help
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:  15
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:  15
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:  11
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
narmafotinib Small molecule or natural product Hs Inhibition 9.7 pKd 6
⤷ pKd 9.7 (Kd 2.1x10-10 M) [6]
VS-4718 Small molecule or natural product Primary target of this compound Hs Inhibition 8.8 pIC50 14
⤷ pIC50 8.8 (IC50 1.5x10-9 M) [14]
PF-562271 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.8 pIC50 11
⤷ pIC50 8.8 (IC50 1.5x10-9 M) [11]
CEP-37440 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 9
⤷ pIC50 8.7 (IC50 2x10-9 M) [9]
NVP-TAE 226 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 8,12
⤷ pIC50 8.3 (IC50 5.5x10-9 M) [8,12]
YHJ1039 Small molecule or natural product Hs Inhibition 8.1 pIC50 3
⤷ pIC50 8.1 (IC50 7x10-9 M) [3]
conteltinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >7.7 pIC50 17
⤷ pIC50 >7.7 (IC50 <2x10-8 M) [17]
Description: In a time-resolved fluorescence (TRF) assay using recombinant GST-tagged FAK.
ENMD-2076 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 10
⤷ pIC50 7.3 (IC50 5.5x10-8 M) [10]
compound 30 [PMID: 23414845] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 6.2 pIC50 15
⤷ pIC50 6.2 (IC50 6.4x10-7 M) [15]
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: 4,16
Key to terms and symbols Click column headers to sort
Target used in screen: FAK
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.0 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
BI-2536 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand 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 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: FAK/FAK(PTK2)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.3 5.5 -0.5
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 23.5 105.0 67.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 25.3 20.0 -1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 25.8 15.0 4.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 27.0
SU6656 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 33.1 21.0 8.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 35.0 16.0 1.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 35.3 51.0 9.0
Syk inhibitor II Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 44.0 64.0 7.0
isogranulatimide Small molecule or natural product 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 [7,13]. Targeted FAK inhibition potentiates the efficacy of checkpoint immunotherapy in pancreatic cancers [7].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
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. 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. Cho H, Shin I, Yoon H, Jeon E, Lee J, Kim Y, Ryu S, Song C, Kwon NH, Moon Y et al.. (2021) Identification of Thieno[3,2-d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3. J Med Chem, 64 (16): 11934-11957. [PMID:34324343]

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. Holmes IP, Bergman Y, Lunniss GE, Nikac M, Chol N, Hemley CF, Walker SR, Foitzik RC, Ganame D, Lessene R. (2015) Selective FAK inhibitors. Patent number: US9120761B2. Assignee: Cancer Therapeutics CRC Pty Ltd. Priority date: 06/07/2012. Publication date: 01/09/2015.

7. 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]

8. 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]

9. 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]

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

11. 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]

12. 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]

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

14. 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]

15. 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]

16. 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]

17. 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 23/11/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2180.