Jones Philip, Altamura Sergio, Chakravarty Prasun K, Cecchetti Ottavia, De Francesco Raffaele, Gallinari Paola, Ingenito Raffaele, Meinke Peter T, Petrocchi Alessia, Rowley Michael, Scarpelli Rita, Serafini Sergio, Steinkühler Christian
IRBM/Merck Research Laboratories, Via Pontina km 30,600, 00040 Pomezia, Italy.
Bioorg Med Chem Lett. 2006 Dec 1;16(23):5948-52. doi: 10.1016/j.bmcl.2006.09.002. Epub 2006 Sep 20.
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.
组蛋白脱乙酰酶（HDAC）抑制剂为癌症治疗提供了一种有前景的策略，第一代HDAC抑制剂目前正处于临床试验阶段。本文描述了一系列基于天然环四肽阿皮西丁的结构新颖的HDAC抑制剂。在样品库中进行筛选以寻找L-2-氨基-8-氧代癸酸（L-Aoda）衍生物，鉴定出一种带有不寻常酮锌结合基团的无环先导分子1。围绕该先导物进行的构效关系（SAR）研究导致优化为强效、低分子量、选择性、非异羟肟酸HDAC抑制剂，其效力与目前的临床候选药物相当。
