Histone deacetylase (HDAC) is an epigenetic enzyme that regulates gene expression through histone deacetylation. It leads to more closed chromatin structure and gene expression inhibition. Many non-histones are also targets of HDAC, such as α Microtubulin, heat shock protein (HSP) 90, and hypoxia-inducible factor HIF-1 α. Specifically, HDAC is divided into five categories: Class I (HDAC 1-3 and 8), Class IIa (HDAC 4, 5, 7 and 9), Class IIb (HDAC 6 and 10), Class III (SIRT 1-7), and Class IV (HDAC 11). Besides, HDACs are usually expressed in almost all tissues. However, HDACi has shown that it can induce specific changes in gene expression and affect a variety of other processes. Furthermore, it includes growth arrest, differentiation, cytotoxicity, and apoptosis induction.
Moreover, HDAC is crucial in the control of gene expression, and its activity disorder is related to a variety of diseases, including cancer, and cardiovascular and nervous system diseases. Meanwhile, the altered HDAC function is related to cancer and neurodegenerative diseases, making HDAC a hot therapeutic target. Now, we will introduce a potent pyridine-containing HDAC inhibitor, MC2590.
MC2590 is a Potent Pyridine-Containing HDAC Inhibitor.
At first, MC2590 is an inhibitor of HDAC1-3, -6, -8, and -10 (class I/IIb-selective inhibitor) with IC50s of 0.015 μM-0.156 μM. Nonetheless, MC2590 also inhibits HDAC isoforms HDAC4, HDAC5, HDAC7, HDAC9, HDAC11 with IC50s of 1.35 μM-3.98 μM. MC2625 induces G2/M cell cycle arrest and modulates pro- and anti-apoptotic microRNAs toward apoptosis induction.
Secondly, MC2625 has antiproliferative activity with Colorectal carcinoma HCT116 (IC50=0.07 μM), Lung adenocarcinoma A549 (IC50=0.32 μM), Chronic myelogenous leukemia K562 (IC50=0.05 μM) for 72 h.
Importantly, MC2625 with 1, 5 μM for 24, 48 h displays mainly G2/M cell cycle arrest.
Thirdly, MC2625 reveals H3K9/14 hyperacetylation activity, increases the acetyl-α-tubulin level, and markedly upregulates the p21 protein. In particular, MC2625 increases mRNA expression of p21, BAX, and BAK, downregulates cyclin D1 and BCL-2 and modulates pro- and anti-apoptotic microRNAs towards apoptosis induction.
Finally, MC2590 is a potent pyridine-containing histone deacetylase (HDAC) inhibitor.
References:
Elisabetta Di Bello, et al. Eur J Med Chem. 2022 Dec 15;247:115022.