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通过基于形状的虚拟筛选和基于结构的分子修饰相结合,发现并设计三环支架作为蛋白激酶 CK2(CK2)抑制剂。

Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.

机构信息

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

出版信息

J Chem Inf Model. 2013 Aug 26;53(8):2093-102. doi: 10.1021/ci400114f. Epub 2013 Aug 12.

Abstract

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.

摘要

蛋白激酶 CK2(CK2)是一种广泛存在的丝氨酸/苏氨酸蛋白激酶,可作用于数百种内源性底物,是一种极具吸引力的抗癌靶点。其最有效的抑制剂之一 CX-4945 已进入 I 期临床试验。本文介绍了一种结合基于形状的虚拟筛选来鉴定新型 CK2 抑制剂的综合工作流程。基于 CX-4945 构建了一个基于形状的模型,随后的虚拟筛选鉴定出了一些与 CX-4945 具有高度形状相似性的新型骨架。其中两个三环骨架,[1,2,4]三唑并[4,3-c]喹唑啉和[1,2,4]三唑并[4,3-a]喹喔啉引起了我们的注意。结合严格的化学相似性分析,基于这两个三环骨架进行了第二轮基于形状的筛选,得到了 28 个衍生物。这些化合物不仅对 CK2 具有强大且剂量依赖性的抑制活性,而且对一系列癌细胞系表现出可接受的抗增殖作用。我们的工作流程提供了一种鉴定新型 CK2 抑制剂的高效策略。本文报道的化合物可以作为进一步修饰的理想先导化合物。

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