Bresciani Alberto, Ontoria Jesus M, Biancofiore Ilaria, Cellucci Antonella, Ciammaichella Alina, Di Marco Annalise, Ferrigno Federica, Francone Alessandra, Malancona Savina, Monteagudo Edith, Nizi Emanuela, Pace Paola, Ponzi Simona, Rossetti Ilaria, Veneziano Maria, Summa Vincenzo, Harper Steven
IRBM Science Park, Via Pontina km 30,600, 00071 Pomezia, Rome, Italy.
ACS Med Chem Lett. 2018 Nov 27;10(4):481-486. doi: 10.1021/acsmedchemlett.8b00517. eCollection 2019 Apr 11.
The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the -anilide that is featured in HDAC3 selective compounds reported to date.
I类组蛋白去乙酰化酶（HDAC）抑制剂作为癌症治疗药物的应用已得到充分确立，但最近它们在非肿瘤适应症方面的研发有所增加。我们在此报告基于乙基酮锌结合基团（ZBG）而非多数HDAC抑制剂所具有的异羟肟酸，生成了改进的I类选择性人HDAC抑制剂。我们还描述了一组新型的HDAC3亚型选择性抑制剂，它们比最常用的HDAC3选择性工具化合物RGFP966表现出更强的效力和选择性。这些化合物同样基于一种与迄今报道的HDAC3选择性化合物中所具有的酰胺基不同的替代ZBG。
