Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930
Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930
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DOI：
10.1016/j.bmcl.2011.08.070
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发表时间：
2011-11-01
影响因子：
2.7
通讯作者：
Korlipara, Vijaya L.
中科院分区：
文献类型：
--
作者：
Patel, Jay P.;Kuang, Ye-Hong;Korlipara, Vijaya L.
为了进一步了解OSI-930的SAR以及c-Kit和KDR的结合位点特征，对OSI-930的喹啉结构域进行了修饰，OSI-930是受体酪氨酸激酶（RTK）c-Kit和KDR的双重抑制剂。合成了一系列具有杂原子取代的吡啶基和苯环系统的16种化合物，并针对一组激酶（包括c-Kit和KDR）进行了评价。发现氨基吡啶基衍生物6是该系列中活性最高的成员，在10 μ M和1 μ M时分别对c-Kit具有91%和57%的抑制，在10 μ M和1 μ M时分别对KDR具有88%和50%的抑制。还测试了目标化合物通过抑制ATP依赖性ABCG 2泵来抑制米托蒽醌外排的能力。硝基吡啶衍生物5和邻硝基苯基衍生物7表现出对ABCG 2泵的完全抑制，IC 50值分别为13.67 μ M和16.67 μ M。(C)2011爱思唯尔有限公司保留所有权利。
The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with heteroatom substituted pyridyl and phenyl ring systems was synthesized and evaluated against a panel of kinases including c-Kit and KDR. Aminopyridyl derivative 6 was found to be the most active member of the series with 91% and 57% inhibition of c-Kit at 10 mu M and 1 mu M, respectively and 88% and 50% inhibition of KDR at 10 mu M and 1 mu M, respectively. The target compounds were also tested for their ability to inhibit efflux of mitoxantrone through inhibition of ATP dependent ABCG2 pump. Nitropyridyl derivative 5 and o-nitrophenyl derivative 7 exhibited complete inhibition of the ABCG2 pump with IC50 values of 13.67 mu M and 16.67 mu M, respectively. (C) 2011 Elsevier Ltd. All rights reserved.