采用从头至尾方法鉴定的新型 VEGFR-2 激酶抑制剂。
Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach.
机构信息
Excellent Center for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudya Rd, Bangkok 10400, Thailand.
出版信息
Bioorg Med Chem Lett. 2013 May 15;23(10):2962-7. doi: 10.1016/j.bmcl.2013.03.042. Epub 2013 Mar 20.
Abstract
We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1,2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization.
摘要
我们报告了一种新型的 VEGFR-2 抑制剂，它是通过背向向前的方法开发的。对接实验表明，先导化合物的 3-氯甲基苯脲基序占据了 VEGFR-2 激酶的后袋。我们试图通过使用三唑连接子扩展结构来进入前袋，从而增强 1 的结合亲和力。在计算机中筛选了 1,4-（取代）-1H-1,2,3-三唑库，发现一种化合物（VH02）对 VEGFR-2 的 IC50 为 0.56μM。VH02 表现出抗血管生成作用，在 0.3μM 时抑制 HUVEC 细胞（EA.hy926）的管形成，比其细胞毒性剂量低 13 倍。这些酶和细胞活性表明，VH02 具有作为进一步优化的潜在先导物的潜力。
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