Abstract：
A promising hydrazide based small molecule lead as a potent and selective histone deacetylase 3 (HDAC3) inhibitor has been developed from a small series of synthesized novel chemical entities. The lead compound (4e) displayed high HDAC3 inhibitory potency (IC50 = 15.41 nM) and a minimum of 18-fold selectivity over other HDAC isoforms. It also exhibited potent cytotoxicity against several cancer cell lines with minimal toxicity against normal cell lines tested. Compound 4e also enhanced acetylation levels on H3K9, H4K12 and H3K27 both in vitro and in vivo. It also induced cell cycle arrest at the G2/M phase in B16F10 and 4T1 cells. It caused significant apoptosis and upregulated the expression of caspase-3, caspase-7, cytochrome c and downregulated the expression of BCL2 in tumour tissue. In addition, the downregulation of CD44, EGFR and Ki-67 suggested the potential of compound 4e in reducing cell proliferation and metastasis in mice. Further, a marked decrease in the tumour volume was observed with no general toxicity in the major organs when treated with 4e in the 4T1-Luc xenograft mouse model. Therefore, compound 4e is a promising candidate selectively targeting HDAC3 with a significant antitumour activity that can be evaluated further in preclinical and clinical evaluation.
摘要：
已经从一系列合成的新型化学实体中开发了一种有前途的基于酰肼的小分子铅作为有效和选择性的组蛋白脱乙酰酶3（HDAC3）抑制剂。先导化合物(4e)显示出高的HDAC3抑制效力(IC50=15.41nM)和比其他HDAC同工型至少18倍的选择性。它还对几种癌细胞系表现出有效的细胞毒性，对正常细胞系的毒性最小。化合物4e还在体外和体内增强了对H3K9、H4K12和H3K27的乙酰化水平。它还在B16F10和4T1细胞中诱导细胞周期停滞在G2/M期。它引起明显的细胞凋亡，并上调caspase-3，caspase-7，细胞色素c的表达，并下调肿瘤组织中BCL2的表达。此外,CD44、EGFR和Ki-67的下调表明化合物4e在小鼠中降低细胞增殖和转移的潜力。Further,当在4T1-Luc异种移植小鼠模型中用4e处理时,观察到肿瘤体积的显著减小,在主要器官中没有一般毒性。因此,化合物4e是选择性靶向HDAC3的有希望的候选物,具有显著的抗肿瘤活性,其可以在临床前和临床评价中进一步评价。
