Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer.
Development of keratinocyte growth factor receptor tyrosine kinase inhibitors for the treatment of cancer.
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发表时间：
2007-11
影响因子：
2
通讯作者：
J. Hackett;Zili Xiao;X. Zang;M. Lerner;D. Brackett;R. Brueggemeier;Pui-Kai Li;J. Pento
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文献类型：
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作者：
J. Hackett;Zili Xiao;X. Zang;M. Lerner;D. Brackett;R. Brueggemeier;Pui-Kai Li;J. Pento
背景技术成年雌性动物的乳腺对角质形成细胞生长因子(KGF)非常敏感。 KGF 作用于 KGF 受体 (KGFR)，对乳腺癌细胞增殖和运动产生快速而深刻的刺激。此外，KGF 诱导的乳腺癌细胞运动是通过 Erk1/2 信号通路介导的。因此，KGF/KGFR信号转导的增强可能是乳腺癌转移进展的早期步骤。 KGFR 受体模型用于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 化合物的合成和生物活性。材料和方法 KGFR 的计算机建模用于创建具有与 KGFR 高亲和力结合潜力的化合物虚拟库。本研究合成并测试了其中三种化合物。使用培养物损伤试验测试了这些化合物抑制 KGF 介导的乳腺癌细胞增殖和运动的能力。此外，使用免疫细胞化学测量了最有效的 KGFR TKI 化合物对细胞膜 KGFR 相对密度的影响。结果 正如计算机模型预测的那样，KGFR TKI 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。结论 本项目中鉴定的新型抑制剂是选择性 KGFR 抑制剂，它们似乎可以降低癌细胞上 KGFR 的表达。这些结果可能导致开发一类新型抗癌药物，用于化学预防转移性癌症的发展，并提供治疗乳腺癌的新方法。
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.