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PDBsum entry 3bz3
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protein ligands links
Transferase PDB id
3bz3

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
259 a.a. *
Ligands
YAM
Waters ×281
* Residue conservation analysis
PDB id:
3bz3
Name: Transferase
Title: Crystal structure analysis of focal adhesion kinase with a methanesulfonamide diaminopyrimidine inhibitor
Structure: Focal adhesion kinase 1. Chain: a. Fragment: kinase domain. Synonym: fadk 1, pp125fak, protein-tyrosine kinase 2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptk2, fak, fak1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.20Å     R-factor:   0.160     R-free:   0.234
Authors: F.Vajdos,E.Marr
Key ref: W.G.Roberts et al. (2008). Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res, 68, 1935-1944. PubMed id: 18339875 DOI: 10.1158/0008-5472.CAN-07-5155
Date:
17-Jan-08     Release date:   01-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q05397  (FAK1_HUMAN) -  Focal adhesion kinase 1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1052 a.a.
259 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1158/0008-5472.CAN-07-5155 Cancer Res 68:1935-1944 (2008)
PubMed id: 18339875  
 
 
Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.
W.G.Roberts, E.Ung, P.Whalen, B.Cooper, C.Hulford, C.Autry, D.Richter, E.Emerson, J.Lin, J.Kath, K.Coleman, L.Yao, L.Martinez-Alsina, M.Lorenzen, M.Berliner, M.Luzzio, N.Patel, E.Schmitt, S.LaGreca, J.Jani, M.Wessel, E.Marr, M.Griffor, F.Vajdos.
 
  ABSTRACT  
 
Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21482721 M.Vicente-Manzanares, K.Newell-Litwa, A.I.Bachir, L.A.Whitmore, and A.R.Horwitz (2011).
Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front-back polarity in migrating cells.
  J Cell Biol, 193, 381-396.  
20308429 A.M.Pasapera, I.C.Schneider, E.Rericha, D.D.Schlaepfer, and C.M.Waterman (2010).
Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation.
  J Cell Biol, 188, 877-890.  
20001213 C.A.Lipinski, and J.C.Loftus (2010).
Targeting Pyk2 for therapeutic intervention.
  Expert Opin Ther Targets, 14, 95.  
  20234193 C.Walsh, I.Tanjoni, S.Uryu, A.Tomar, J.O.Nam, H.Luo, A.Phillips, N.Patel, C.Kwok, G.McMahon, D.G.Stupack, and D.D.Schlaepfer (2010).
Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models.
  Cancer Biol Ther, 9, 778-790.  
  20160475 E.A.Beierle, X.Ma, J.Stewart, C.Nyberg, A.Trujillo, W.G.Cance, and V.M.Golubovskaya (2010).
Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma.
  Cell Cycle, 9, 1005-1015.  
  20234191 I.Tanjoni, C.Walsh, S.Uryu, A.Tomar, J.O.Nam, A.Mielgo, S.T.Lim, C.Liang, M.Koenig, C.Sun, N.Patel, C.Kwok, G.McMahon, D.G.Stupack, and D.D.Schlaepfer (2010).
PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments.
  Cancer Biol Ther, 9, 764-777.  
20966971 M.C.Frame, H.Patel, B.Serrels, D.Lietha, and M.J.Eck (2010).
The FERM domain: organizing the structure and function of FAK.
  Nat Rev Mol Cell Biol, 11, 802-814.  
20802523 M.K.Wendt, J.A.Smith, and W.P.Schiemann (2010).
Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression.
  Oncogene, 29, 6485-6498.  
20947480 M.Quintela-Fandino, A.González-Martín, and R.Colomer (2010).
Targeting cytoskeleton reorganisation as antimetastatic treatment.
  Clin Transl Oncol, 12, 662-669.  
20802517 S.Ocak, H.Yamashita, A.R.Udyavar, A.N.Miller, A.L.Gonzalez, Y.Zou, A.Jiang, Y.Yi, Y.Shyr, L.Estrada, V.Quaranta, and P.P.Massion (2010).
DNA copy number aberrations in small-cell lung cancer reveal activation of the focal adhesion pathway.
  Oncogene, 29, 6331-6342.  
  20616959 V.Bolós, J.M.Gasent, S.López-Tarruella, and E.Grande (2010).
The dual kinase complex FAK-Src as a promising therapeutic target in cancer.
  Onco Targets Ther, 3, 83-97.  
20530207 X.Zhao, X.Peng, S.Sun, A.Y.Park, and J.L.Guan (2010).
Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.
  J Cell Biol, 189, 955-965.  
19708661 D.Wang, H.C.Chuang, S.C.Weng, P.H.Huang, H.Y.Hsieh, S.K.Kulp, and C.S.Chen (2009).
alpha-Tocopheryl succinate as a scaffold to develop potent inhibitors of breast cancer cell adhesion.
  J Med Chem, 52, 5642-5648.  
19610651 E.V.Kurenova, D.L.Hunt, D.He, A.T.Magis, D.A.Ostrov, and W.G.Cance (2009).
Small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo.
  J Med Chem, 52, 4716-4724.  
20014455 H.F.Hao, Y.Naomoto, X.H.Bao, N.Watanabe, K.Sakurama, K.Noma, Y.Tomono, T.Fukazawa, Y.Shirakawa, T.Yamatsuji, J.Matsuoka, and M.Takaoka (2009).
Progress in researches about focal adhesion kinase in gastrointestinal tract.
  World J Gastroenterol, 15, 5916-5923.  
19671741 J.K.Slack-Davis, E.D.Hershey, D.Theodorescu, H.F.Frierson, and J.T.Parsons (2009).
Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model.
  Mol Cancer Ther, 8, 2470-2477.  
19734908 J.S.Desgrosellier, L.A.Barnes, D.J.Shields, M.Huang, S.K.Lau, N.Prévost, D.Tarin, S.J.Shattil, and D.A.Cheresh (2009).
An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression.
  Nat Med, 15, 1163-1169.  
19141060 J.Xia, N.Lv, Y.Hong, C.Li, X.Tao, X.Chen, and B.Cheng (2009).
Increased expression of focal adhesion kinase correlates with cellular proliferation and apoptosis during 4-nitroquinoline-1-oxide-induced rat tongue carcinogenesis.
  J Oral Pathol Med, 38, 524-529.  
19169797 J.Zhao, and J.L.Guan (2009).
Signal transduction by focal adhesion kinase in cancer.
  Cancer Metastasis Rev, 28, 35-49.  
19740433 M.K.Wendt, and W.P.Schiemann (2009).
Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-beta signaling and metastasis.
  Breast Cancer Res, 11, R68.  
19190626 Y.Xu, N.Benlimame, J.Su, Q.He, and M.A.Alaoui-Jamali (2009).
Regulation of focal adhesion turnover by ErbB signalling in invasive breast cancer cells.
  Br J Cancer, 100, 633-643.  
18778562 C.Khanna (2008).
Novel targets with potential therapeutic applications in osteosarcoma.
  Curr Oncol Rep, 10, 350-358.  
19030106 D.Lietha, and M.J.Eck (2008).
Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation.
  PLoS ONE, 3, e3800.
PDB codes: 2jkk 2jkm 2jko 2jkq
18391070 S.M.Weis, S.T.Lim, K.M.Lutu-Fuga, L.A.Barnes, X.L.Chen, J.R.Göthert, T.L.Shen, J.L.Guan, D.D.Schlaepfer, and D.A.Cheresh (2008).
Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK.
  J Cell Biol, 181, 43-50.  
  18677107 S.T.Lim, D.Mikolon, D.G.Stupack, and D.D.Schlaepfer (2008).
FERM control of FAK function: implications for cancer therapy.
  Cell Cycle, 7, 2306-2314.  
18989950 V.M.Golubovskaya, C.Nyberg, M.Zheng, F.Kweh, A.Magis, D.Ostrov, and W.G.Cance (2008).
A small molecule inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the y397 site of focal adhesion kinase decreases tumor growth.
  J Med Chem, 51, 7405-7416.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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