Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.
Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.
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DOI：
10.1021/acs.jmedchem.5b01632
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发表时间：
2016-01
影响因子：
7.3
通讯作者：
D. Reddy;F. Ballante;Timothy Chuang;Adele Pirolli;B. Marrocco;G. Marshall
中科院分区：
文献类型：
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作者：
D. Reddy;F. Ballante;Timothy Chuang;Adele Pirolli;B. Marrocco;G. Marshall
在保持效力的同时选择性抑制 KDAC 亚型仍然是一个挑战。使用拉格唑大环缩酚肽结构作为开发具有更高选择性的新型 KDACIs 的起点，设计、合成了四种不同的简化拉格唑类似物 (SLA) 支架与不同锌结合基团（总共 60 种化合物）的组合，并针对 I 类 KDAC 1、3 和 8 以及 II 类 KDAC6 进行了评估。实验证据以及分子对接表明，通过影响 KDAC 活性位点中锌结合基团的正确排列，环状四肽 (CTP) 是效力和选择性的主要决定因素，为开发具有更高异构体选择性和效力的新 KDACIs 提供了进一步的基础。
Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.