FMS-like tyrosine kinase 3 (FLT3) inhibitors: Molecular docking and experimental studies
FMS-like tyrosine kinase 3 (FLT3) inhibitors: Molecular docking and experimental studies
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DOI：
10.1016/j.ejphar.2016.02.048
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发表时间：
2016-04-05
影响因子：
5
通讯作者：
Griffith, Renate
中科院分区：
文献类型：
--
作者：
Mashkani, Baratali;Tanipour, Mohammad Hossein;Griffith, Renate
25%的急性淋巴细胞性白血病和30%的急性髓系白血病患者存在FMS样酪氨酸激酶3(Flt3)的激活突变。因此，Flt3是一种潜在的小分子激酶抑制剂的治疗靶点。在这项研究中，通过同源模拟和分子对接，获得了Flt3与激酶抑制剂(CEP701、PKC412、苏尼替尼、伊马替尼和达沙替尼)之间的蛋白质-配体相互作用。通过在FDC-P1细胞中表达野生型和内部串联复制突变体Flt3(Flt3-WT和Flt3-ITD)，建立了用于实验检测抑制剂的细胞系统。伊马替尼和达沙替尼无法与任何Flt3模型对接，这与它们在实验检测中缺乏活性是一致的。CEP701、PKC412和Sunitinib与Flt3的ATP结合口袋相互作用，与Cys694和G1u692形成氢键。根据细胞增殖实验的EC50值，CEP701的抑制作用最强，舒尼替尼和PKC412分别排在第二和第三位。选择性最强的是舒尼替尼，其次是PKC421和CEP701。舒尼替尼和CEP701对Flt3自磷酸化的抑制作用低于对细胞增殖的抑制，提示抑制Flt3下游蛋白可能参与了细胞作用。这项研究表明，对接过程能够区分Flt3抑制剂和无效化合物。此外，与ATP结合口袋中的磷酸结合区域的相互作用增加了效力，但代价是选择性。这些发现可用于设计高效和选择性的Flt3和其他相关激酶的抑制剂。(C)2016爱思唯尔B.V.保留所有权利。
Activating mutations in FMS-like tyrosine kinase 3 (FLT3) occur in 25% of acute lymphoid and 30% of acute myeloid leukaemia cases. Therefore, FLT3 is a potential therapeutic target for small molecule kinase inhibitors. In this study, protein-ligand interactions between FLT3 and kinase inhibitors (CEP701, PKC412, sunitinib, imatinib and dasatinib) were obtained through homology modelling and molecular docking. A cellular system for experimental testing of the inhibitors was also established by expressing wildtype and internal tandem duplication mutant FLT3 (FLT3-WT and FLT3-ITD) in FDC-P1 cells. Imatinib and dasatinib could not be docked into any of the FLT3 models, consistent with their lack of activity in the experimental assays. CEP701, PKC412 and sunitinib interacted with the ATP-binding pocket of FLT3, forming H-bonds with Cys694 and G1u692. Based on the EC50 values in the cell proliferation assay, CEP701 was the most potent inhibitor; sunitinib and PKC412 were ranked second and third, respectively. Sunitinib was the most selective inhibitor, followed by PKC421 and CEP701. The potency of sunitinib and to a lesser extent CEP701 in inhibition of FLT3 autophosphorylation was lower than the cell proliferation inhibition, indicating that inhibition of FLT3 downstream proteins may contribute to the cellular effects. It was shown in this study that the docking procedure was able to differentiate FLT3 inhibitors from ineffective compounds. Additionally, interaction with the phosphate binding region in the ATP-binding pocket increased potency at the cost of selectivity. These findings can be applied in designing highly effective and selective inhibitors for FLT3 and other related kinases. (C) 2016 Elsevier B.V. All rights reserved.