School of Biomedical Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
Bioorg Med Chem. 2010 Mar 1;18(5):1789-97. doi: 10.1016/j.bmc.2010.01.056. Epub 2010 Jan 28.
Imatinib, dasatinib, sunitinib, CEP-701, and PKC-412, ATP-competitive small molecule inhibitors of type III receptor tyrosine kinases c-KIT and/or FLT3, were evaluated for binding to the closely related receptor, FMS, by docking into models of inactive and active conformations of the FMS kinase domain. To confirm the docking predictions, the drugs were tested for their activity and selectivity in inhibiting cell proliferation and FMS phosphorylation upon stimulation by the FMS ligand, CSF-1. All five drugs inhibited FMS activity. Imatinib, dasatinib and CEP-701 represent three different types of interactions determining drug potency and selectivity.
伊马替尼、达沙替尼、舒尼替尼、CEP-701 和 PKC-412 是 III 型受体酪氨酸激酶 c-KIT 和/或 FLT3 的 ATP 竞争性小分子抑制剂，通过对接 FMS 激酶结构域的无活性和活性构象模型来评估它们与密切相关的受体 FMS 的结合。为了证实对接预测，测试了这些药物在刺激 FMS 配体 CSF-1 后抑制细胞增殖和 FMS 磷酸化的活性和选择性。五种药物均抑制 FMS 活性。伊马替尼、达沙替尼和 CEP-701 代表三种不同类型的相互作用，决定了药物的效力和选择性。
