Hackett John, Xiao Zili, Zang Xiao-Ping, Lerner Megan L, Brackett Daniel J, Brueggemeier Robert W, Li Pui-Kai, Pento J Thomas
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma 73117, USA.
Anticancer Res. 2007 Nov-Dec;27(6B):3801-6.
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.
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.
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.
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.
成年雌性动物的乳腺对角质形成细胞生长因子（KGF）极为敏感。KGF作用于KGF受体（KGFR），可迅速且显著地刺激乳腺癌细胞增殖和迁移。此外，KGF诱导的乳腺癌细胞迁移是通过Erk1/2信号通路介导的。因此，增强KGF/KGFR信号转导可能是乳腺癌转移进展的早期步骤。利用KGFR的受体模型来鉴定具有高受体亲和力的选择性KGFR酪氨酸激酶抑制剂（TKI）分子。本研究描述了三种KGFR TKI化合物的合成及生物活性。
利用KGFR的计算机模型创建一个可能与KGFR高亲和力结合的化合物虚拟库。本研究合成并测试了其中三种化合物。使用细胞划痕实验测试这些化合物抑制KGF介导的乳腺癌细胞增殖和迁移的能力。此外，使用免疫细胞化学方法测定最有效的KGFR TKI化合物对细胞膜KGFR相对密度的影响。
观察到KGFR TKIs如计算机模型预测的那样降低了KGF介导的活性。此外，最有效的抑制剂还降低了癌细胞膜上KGFR的密度。
本项目中鉴定出的新型抑制剂是选择性KGFR抑制剂，似乎能降低癌细胞上KGFR的表达。这些结果可能会促成一类新型抗癌药物的研发，用于化学预防转移性癌症的发展，并为乳腺癌治疗提供新方法。
