Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
Eur J Med Chem. 2022 Aug 5;238:114470. doi: 10.1016/j.ejmech.2022.114470. Epub 2022 May 18.
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 (IC = 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.
一种有前景的基于酰腙的小分子先导化合物被开发出来，作为一种有效的、选择性的组蛋白去乙酰化酶 3（HDAC3）抑制剂，它是从小系列新合成的化学实体中发展而来的。先导化合物（4e）表现出高 HDAC3 抑制活性（IC=15.41 nM），对其他 HDAC 同工酶具有至少 18 倍的选择性。它还对几种癌细胞系表现出很强的细胞毒性，对测试的正常细胞系的毒性最小。化合物 4e 还能在体外和体内增强 H3K9、H4K12 和 H3K27 的乙酰化水平。它还能诱导 B16F10 和 4T1 细胞的细胞周期停滞在 G2/M 期。它能引起显著的细胞凋亡，并上调肿瘤组织中 caspase-3、caspase-7、细胞色素 c 的表达，下调 BCL2 的表达。此外，CD44、EGFR 和 Ki-67 的下调表明，化合物 4e 具有在小鼠中减少细胞增殖和转移的潜力。此外，在 4T1-Luc 异种移植小鼠模型中，用 4e 治疗时，主要器官没有明显的毒性，肿瘤体积明显减小。因此，化合物 4e 是一种有前景的候选药物，它能选择性地靶向 HDAC3，具有显著的抗肿瘤活性，可在临床前和临床评估中进一步评估。
