In conclusion while class I HDAC inhibitors

In conclusion, while class I HDAC inhibitors, isoform-specific HDAC3 and HDAC6 inhibitors may represent novel therapeutic targets for prevention of clinical AF onset and progression, the specific HDAC3 and HDAC6 inhibitors may be more appropriate because of their limited off-targets effects. Besides pharmacological treatment, low-carbohydrate ketogenic diet and exercise, which increase the abundance of the endogenous HDAC inhibitor, βOHB, may also help to reduce especially the inflammatory-related AF persistence [97,99,100].
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Introduction Alterations of epigenetic modifications (e.g., DNA methylation and histone modifications) play important roles in the initiation and progression of human cancers, providing attractive biomarkers and targets for diagnostic and therapeutic purposes [1], [2], [3], [4], [5]. Generally, epigenetic control is involved in all of the hallmarks of tumorigenesis and survival (e.g., sustaining proliferation, inducing angiogenesis, activating invasion and metastasis) [6], [7], therefore epigenetic therapy can concurrently modulate and reverse multiple aberrant signaling pathways, inducing widespread changes in gene expression and multiple antitumor biological processes [8]. In the past few years, targeting epigenetic variation to reverse epigenome abnormalities has been widely recognized as a practical therapeutic strategy for cancer and other human disease such as inflammation, neurological, autoimmune and cardiovascular diseases [9], [10], [11], [12]. DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which separately catalyze the methylation of CpG islands in DNA and deacetylation in histones and other substrate proteins, are the most studied and recognized epigenetic targets for antitumor agents discovery [13], [14], [15], [16], [17]. Now two DNMT inhibitors (DNMTi) (i.e., azacytidine and decitabine) and five HDAC inhibitors (HDACi) (i.e., vorinostat, depsipeptide, belinostat, panobinostat, and chidamide) have been approved for cancer therapy. The abnormalities of DNMT and HDAC are both linked to the decreased expression of tumor suppressor genes (TSGs) in human cancers. Besides, DNMT and HDAC are closely related in cellular biology [18], [19], [20], [21]. The interplay of DNA methylation and histone de-acetylation reinforces the silence of TSGs and poses a challenge for the durability of DNMTi and HDACi used as single agents, attributing to that either aberration could be the Boc-D-FMK driver for tumorigenesis and survival [22]. It has been reported that DNA methylation may give rise to acquired resistance for HDACi [23]. On the other hands, researches demonstrated that combination therapies consisting of DNMTi and HDACi showed significant synergistic antitumor effect, including suppressing the tumorigenicity of cancer stem-like cells and enhancing cancer immune therapy [24], [25], [26], [27], [28]. Hence we proposed that developing multi-target inhibitors against DNMT and HDAC simultaneously might be an alternative approach for cancer treatments. Multitarget drugs might overcome resistance and improve outcomes vs single-target agents, and have more predictable pharmacokinetic (PK) and pharmacodynamic (PD) and lower toxicities vs drug combinations [29], [30], [31], [32], [33]. As a part of our ongoing development of multitarget antitumor agents [34], [35], [36], [37], [38], we previously reported compound 15a as a DNMT and HDAC dual inhibitor with potent HDAC inhibitory activity and potential DNMT inhibitory potency [39]. In the present study, we designed and synthesized a novel DNMT and HDAC dual inhibitor, C02S, based on rational drug design strategy. Our data documented that C02S had good DNMT/HDAC enzymatic inhibitory potency and significant antitumor activity against breast cancer cells by modulating multiple cancer hallmarks, warranting C02S as a promising antitumor lead compound.
Rational design and synthesis Generally, HDAC inhibitors share similar pharmacophore characteristics consisting of three groups: a cap group to occlude the entrance of the active site pocket; a zinc-binding group (ZBG) to chelate the zinc ion in the active catalytic site; and a linker to connect the cap group and ZBG [31], [39]. On the other hand, DC-517 and its S- and R- enantiomers are selective DNMT1 inhibitors reported by Luo’s group [40] with IC50 values of 1.7, 2.5, 1.8 µM, respectively. These compounds consist of two carbazole groups and a side chain, within which the hydroxyl group is critical to form an essential hydrogen bond interaction with DNMT1. Herein we intend to introduce the hydroxamic acid group to the end of the side chain, with not changing the carbazole groups and the hydroxyl group. In our opinion, our target compounds C02 and its enantiomers (R)-C02 and (S)-C02 possess the general functional group characteristics of HDACi warranting them to be potential HDAC inhibitors; besides, the similar molecular scaffold with DC-517 would be helpful to bind with DNMT (Scheme 1).