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Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer.
Anticancer Res. 2007 Nov-Dec; 27(6B):3801-6.AR

Abstract

BACKGROUND

The mammary glands of adult female animals are remarkably sensitive to keratinocyte growth factor (KGF). KGF acts at the KGF receptor (KGFR) to produce a rapid and profound stimulation of breast cancer cell proliferation and motility. Further, KGF-induced motility in breast cancer cells is mediated via the Erk1/2 signaling pathway. Thus, enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase inhibitor (TKI) molecules with high receptor affinity. The present study describes the synthesis and biological activity of three of the KGFR TKI compounds.

MATERIALS AND METHODS

Computer modeling of the KGFR was used to create a virtual library of compounds that have the potential to bind with high affinity to the KGFR. Three of these compounds were synthesized and tested in this study. The compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation and motility using a culture wounding assay. In addition, the effect of the most potent KGFR TKI compound on the relative density of cell membrane KGFR was measured using immunocytochemistry.

RESULTS

It was observed that the KGFR TKIs decreased KGF-mediated activity as predicted by computer modeling. In addition, the most potent inhibitor also reduced the density of the KGFR on the membrane of the cancer cells.

CONCLUSION

The novel inhibitors identified in this project are selective KGFR inhibitors which appear to reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the chemoprevention of metastatic cancer development and provide a new approach in the treatment of breast cancer.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma 73117, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18225535

Citation

Hackett, John, et al. "Development of Keratinocyte Growth Factor Receptor Tyrosine Kinase Inhibitors for the Treatment of Cancer." Anticancer Research, vol. 27, no. 6B, 2007, pp. 3801-6.
Hackett J, Xiao Z, Zang XP, et al. Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer. Anticancer Res. 2007;27(6B):3801-6.
Hackett, J., Xiao, Z., Zang, X. P., Lerner, M. L., Brackett, D. J., Brueggemeier, R. W., Li, P. K., & Pento, J. T. (2007). Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer. Anticancer Research, 27(6B), 3801-6.
Hackett J, et al. Development of Keratinocyte Growth Factor Receptor Tyrosine Kinase Inhibitors for the Treatment of Cancer. Anticancer Res. 2007 Nov-Dec;27(6B):3801-6. PubMed PMID: 18225535.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer. AU - Hackett,John, AU - Xiao,Zili, AU - Zang,Xiao-Ping, AU - Lerner,Megan L, AU - Brackett,Daniel J, AU - Brueggemeier,Robert W, AU - Li,Pui-Kai, AU - Pento,J Thomas, PY - 2008/1/30/pubmed PY - 2008/2/13/medline PY - 2008/1/30/entrez SP - 3801 EP - 6 JF - Anticancer research JO - Anticancer Res VL - 27 IS - 6B N2 - BACKGROUND: The mammary glands of adult female animals are remarkably sensitive to keratinocyte growth factor (KGF). KGF acts at the KGF receptor (KGFR) to produce a rapid and profound stimulation of breast cancer cell proliferation and motility. Further, KGF-induced motility in breast cancer cells is mediated via the Erk1/2 signaling pathway. Thus, enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase inhibitor (TKI) molecules with high receptor affinity. The present study describes the synthesis and biological activity of three of the KGFR TKI compounds. MATERIALS AND METHODS: Computer modeling of the KGFR was used to create a virtual library of compounds that have the potential to bind with high affinity to the KGFR. Three of these compounds were synthesized and tested in this study. The compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation and motility using a culture wounding assay. In addition, the effect of the most potent KGFR TKI compound on the relative density of cell membrane KGFR was measured using immunocytochemistry. RESULTS: It was observed that the KGFR TKIs decreased KGF-mediated activity as predicted by computer modeling. In addition, the most potent inhibitor also reduced the density of the KGFR on the membrane of the cancer cells. CONCLUSION: The novel inhibitors identified in this project are selective KGFR inhibitors which appear to reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the chemoprevention of metastatic cancer development and provide a new approach in the treatment of breast cancer. SN - 0250-7005 UR - https://www.unboundmedicine.com/medline/citation/18225535/Development_of_keratinocyte_growth_factor_receptor_tyrosine_kinase_inhibitors_for_the_treatment_of_cancer_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=18225535 DB - PRIME DP - Unbound Medicine ER -