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PF-562271

Description of PF-562271: PF-562271  is an orally bioavailable small molecule and ATP-competitive focal adhesion kinase (FAK) inhibitor with potential antineoplastic and antiangiogenic activities. FAK inhibitor PF-00562271 inhibits the tyrosine kinase FAK, and to a lesser extent, proline-rich tyrosine kinase (PYK2), which may inhibit tumor cell migration, proliferation, and survival. As FAK is a signal transducer for integrins, inhibition of FAK by this agent may prevent integrin-mediated activation of several downstream signals including ERK, JNK/MAPK and PI3K/Akt. FAK and PYK2, upregulated in many tumor cell types, are involved in tumor cell invasion, migration and proliferation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Pfizer

PF-562,271 activity data:

IC50 (FAK) = 1.5 nmol/L

IC50 (Pyk2 ) = 14 nmol/L

IC50 (phospho-FAK) = 5 nmol/L.

EC50 (FAK phosphorylation) =  93 ng/m

 [source: Cancer Res. 2008 Mar 15;68(6):1935-44.]

Highlight on recent research using PF-562,271

PF-562,271 inhibits the growth and metastasis of pancreatic cancer (data published in 2011): Recent research showed that PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. (source: Mol Cancer Ther. 2011 Nov;10(11):2135-45.)

PF-562,271, preclinical study in PC3M-luc-C6 xenograft models. (data published in 2010):  After two weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854% vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo. (source:Cancer Biol Ther. 2010 July 1; 10(1): 38–43.).

1: Stokes JB, Adair SJ, Slack-Davis JK, Walters DM, Tilghman RW, Hershey ED, Lowrey B, Thomas KS, Bouton AH, Hwang RF, Stelow EB, Parsons JT, Bauer TW. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther. 2011 Nov;10(11):2135-45. Epub 2011 Sep 8. PubMed PMID: 21903606; PubMed Central PMCID: PMC3213273.

2: Serrels A, McLeod K, Canel M, Kinnaird A, Graham K, Frame MC, Brunton VG. The role of FAK catalytic activity on the proliferation and migration of squamous cell carcinoma cells. Int J Cancer. 2011 Aug 5. doi: 10.1002/ijc.26351. [Epub ahead of print] PubMed PMID: 21823119.

3: Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-β-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010 Dec 9;29(49):6485-98. Epub 2010 Aug 30. PubMed PMID: 20802523; PubMed Central PMCID: PMC3076082.

4: Sun H, Pisle S, Gardner ER, Figg WD. Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther. 2010 Jul;10(1):38-43. Epub 2010 Jul 9. PubMed PMID: 20495381; PubMed Central PMCID: PMC3087944.

5: Hao H, Naomoto Y, Bao X, Watanabe N, Sakurama K, Noma K, Motoki T, Tomono Y, Fukazawa T, Shirakawa Y, Yamatsuji T, Matsuoka J, Wang ZG, Takaoka M. Focal adhesion kinase as potential target for cancer therapy (Review). Oncol Rep. 2009 Nov;22(5):973-9. Review. PubMed PMID: 19787209.

6: Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-beta signaling and metastasis. Breast Cancer Res. 2009;11(5):R68. Epub . PubMed PMID: 19740433; PubMed Central PMCID: PMC2790843.

7: Slack-Davis JK, Hershey ED, Theodorescu D, Frierson HF, Parsons JT. Differential requirement for focal adhesion kinase signaling in cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol Cancer Ther. 2009 Aug;8(8):2470-7. Epub 2009 Aug 11. PubMed PMID: 19671741; PubMed Central PMCID: PMC2728172.

8: Bagi CM, Christensen J, Cohen DP, Roberts WG, Wilkie D, Swanson T, Tuthill T, Andresen CJ. Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model. Cancer Biol Ther. 2009 May;8(9):856-65. PubMed PMID: 19458500.

9: Bagi CM, Roberts GW, Andresen CJ. Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases. Cancer. 2008 May 15;112(10):2313-21. PubMed PMID: 18348298.

10: Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, Coleman K, Yao L, Martinez-Alsina L, Lorenzen M, Berliner M, Luzzio M, Patel N, Schmitt E, LaGreca S, Jani J, Wessel M, Marr E, Griffor M, Vajdos F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008 Mar 15;68(6):1935-44. PubMed PMID: 18339875.