Emerging approaches to CDK inhibitor development, a structural perspective.
Emerging approaches to CDK inhibitor development, a structural perspective.
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DOI：
10.1039/d2cb00201a
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发表时间：
2023-02-08
影响因子：
4.1
通讯作者：
Watt, Jessica E.
中科院分区：
文献类型：
--
作者：
Hope, Ian;Endicott, Jane A.;Watt, Jessica E.
细胞周期蛋白依赖性激酶家族的异常活性在许多疾病中经常被注意到，这使它们成为药物开发的潜在靶点。然而，目前的CDK抑制剂缺乏特异性，因为跨家族成员的ATP结合裂解具有很高的序列和结构保守性，这突显了寻找新的CDK抑制模式的必要性。最近，来自X射线结晶学研究的丰富的关于CDK组件和抑制剂络合物的结构信息通过使用冷冻电子显微镜得到补充。这些最新进展为CDK及其相互作用伙伴的功能作用和调控机制提供了深入的见解。本文综述了CDK亚单位的构象延展性、CDK复合体中细小识别位点的重要性、化学诱导CDK降解的进展以及这些研究如何有助于CDK抑制剂的设计。此外，基于片段的药物发现可以用来识别结合到CDK表面变构位置的小分子，采用模仿天然蛋白质-蛋白质相互作用的相互作用。这些在CDK抑制剂机制和化学探针方面的最新结构进展可以为CDK的靶向治疗提供重要的见解。本文综述了CDK的结构特征以及抑制CDK的非ATP竞争性替代方法的最新进展。
Aberrant activity of the cyclin-dependent kinase family is frequently noted in a number of diseases identifying them as potential targets for drug development. However, current CDK inhibitors lack specificity owing to the high sequence and structural conservation of the ATP binding cleft across family members, highlighting the necessity of finding novel modes of CDK inhibition. The wealth of structural information regarding CDK assemblies and inhibitor complexes derived from X-ray crystallographic studies has been recently complemented through the use of cryo-electron microscopy. These recent advances have provided insights into the functional roles and regulatory mechanisms of CDKs and their interaction partners. This review explores the conformational malleability of the CDK subunit, the importance of SLiM recognition sites in CDK complexes, the progress made in chemically induced CDK degradation and how these studies can contribute to CDK inhibitor design. Additionally, fragment-based drug discovery can be utilised to identify small molecules that bind to allosteric sites on the CDK surface employing interactions which mimic those of native protein–protein interactions. These recent structural advances in CDK inhibitor mechanisms and in chemical probes which do not occupy the orthosteric ATP binding site can provide important insights for targeted CDK therapies. This review summarises recent developments in structural characterisation of CDKs and alternative non-ATP competitive ways to inhibit them.
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影响因子：
8.6
作者：
Brand, Matthias;Jiang, Baishan;Winter, Georg E.
通讯作者：
Winter, Georg E.
影响因子：
11.4
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Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
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64.5
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Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
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影响因子：
5.7
作者：
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通讯作者：
Murray, Brion W.