Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design
Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design
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DOI：
10.1021/jm800382h
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发表时间：
2008-08-28
影响因子：
7.3
通讯作者：
Woolford, Alison J. -A.
中科院分区：
文献类型：
--
作者：
Wyatt, Paul G.;Woodhead, Andrew J.;Woolford, Alison J. -A.
将基于片段的筛选技术应用于细胞周期蛋白依赖性激酶2（CDK 2）鉴定了多个（> 30个）有效的、合成上易处理的小分子命中物以用于进一步优化。基于结构的设计方法导致了多个前导序列的鉴定，其保留了初始结合片段的关键相互作用，并另外探索了ATP结合位点的其他区域。本文的大部分内容详细介绍了使用从多个配体-CDK 2共晶结构获得的信息对吲唑（6）进行的结构指导优化。这类化合物的关键结合特征的鉴定导致一系列对CDK 2具有低nM亲和力的分子。细胞活性的优化和药代动力学特性的表征导致了33（AT 7519）的鉴定，其目前正在用于治疗人类癌症的临床试验中进行评估。
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (> 30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.