Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
Anticancer Res. 2010 Dec;30(12):4883-9.
Keratinocyte growth factor (KGF) acts at the KGF receptor (KGFR) to produce a rapid stimulation of breast cancer cell proliferation and motility which is mediated via the Erk signaling pathway. 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 (TK) inhibitor molecules that have the potential to bind selectively to the KGFR. The present study evaluated the biological activity of 57 of these KGFR TK inhibitor compounds on breast cancer cells.
These compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation in MCF-7 breast cancer cells. Furthermore, the effects of the most effective proliferation inhibitors were examined on Erk signaling and on the relative density of cell membrane KGFR.
It was observed that 27 of the 57 compounds tested produced a 20% or greater reduction in KGF-mediated proliferation; while five compounds produced greater than 50% inhibition. In addition, the most potent inhibitors also reduced Erk signaling and cell membrane density of the KGFR.
The compounds examined appear to be selective KGFR inhibitors which inhibit KGF-mediated activity and reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the prevention of metastatic cancer progression.
角质细胞生长因子（KGF）通过 KGF 受体（KGFR）发挥作用，快速刺激乳腺癌细胞增殖和迁移，这一过程是通过 Erk 信号通路介导的。增强 KGF/KGFR 信号转导可能是乳腺癌转移进展的早期步骤。使用 KGFR 受体模型来鉴定选择性的 KGFR 酪氨酸激酶（TK）抑制剂分子，这些分子有可能选择性地与 KGFR 结合。本研究评估了这 57 种 KGFR TK 抑制剂化合物对乳腺癌细胞的生物学活性。
这些化合物被测试其抑制 MCF-7 乳腺癌细胞中 KGF 介导的乳腺癌细胞增殖的能力。此外，还研究了最有效的增殖抑制剂对 Erk 信号和细胞膜 KGFR 相对密度的影响。
观察到 57 种测试化合物中有 27 种使 KGF 介导的增殖减少了 20%或更多；而 5 种化合物产生了超过 50%的抑制。此外，最有效的抑制剂还降低了 Erk 信号和癌细胞表面 KGFR 的密度。
所检查的化合物似乎是选择性的 KGFR 抑制剂，可抑制 KGF 介导的活性并减少癌细胞表面 KGFR 的表达。这些结果可能导致开发一类新型的抗癌剂，用于预防转移性癌症的进展。
