Modulating epigenetic modification has been recognized for over a decade as an effective therapeutic approach to cancer and many studies of histone deacetylase (HDAC), one of the best known epigenetic modulators, have been published. HDAC modulates cell proliferation and angiogenesis and plays an essential role in cell growth. Research shows that up-regulated HDACs are present in many cancer types and synthetic or natural HDAC inhibitors have been used to silence overregulated HDACs. Inhibiting HDACs may cause arrest of cell proliferation, angiogenesis reduction and cell apoptosis. Recent studies indicate that HDAC inhibitors can provide a therapeutic effect in various cancers, such as B-cell lymphoma, leukemia, multiple myeloma and some virus-associated cancers. Some evidence has demonstrated that HDAC inhibitors can increase the expression of immune-related molecules leading to accumulation of CD8 + T cells and causing unresponsive tumor cells to be recognized by the immune system, reducing tumor immunity. This may be a solution for the blockade of PD-1. Here, we review the emerging development of HDAC inhibitors in various cancer treatments and reduction of tumor immunity.

Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which render antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20 000 compounds, by performing a cell-based screening assay, as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents. The results of an in vitro pharmacological study showed that compounds 4 and 8 exhibited the most potent anti-IAV effect with half-maximal effective concentration values of 0.14 and 0.11 μM, respectively, in Madin–Darby canine kidney cells. The mechanism of action studies showed that lead agents 1 and 4 reduced virus replication by directly targeting IAV nucleoproteins and disrupting virus ribonucleoprotein export from the nucleus to the cytosol. On the basis of its high potential as an anti-IAV agent and its selectivity index >785, compound 4 was found to be a promising candidate for further development against IAVs.

The Michael addition reaction is a spontaneous and quick chemical reaction that is widely applied in various fields. This reaction is performed by conjugating an addition of nucleophiles with α, β-unsaturated carbonyl compounds, resulting in the bond formation of C-N, C-S, C-O, and so on. In the development of molecular materials, the Michael addition is not only used to synthesize chemical compounds but is also involved in the mechanism of drug action. Several covalent drugs that bond via Michael addition are regarded as anticarcinogens and anti-inflammatory drugs. Although drug development is mainly focused on pharmaceutical drug discovery, target-based discovery can provide a different perspective for drug usage. However, considerable time and labor are required to define a molecular target through molecular biological experiments. In this review, we systematically examine the chemical structures of current FDA-approved antiviral drugs for potential Michael addition moieties with α, β-unsaturated carbonyl groups, which may exert an unidentified broad-spectrum inhibitory mechanism to target viral or host factors. We thus propose that profiling the targets of antiviral agents, such as Michael addition products, can be achieved by employing a high-throughput LC-MS approach to comprehensively analyze the interaction between drugs and targets, and the subsequent drug responses in the cellular environment to facilitate drug repurposing and/or identify potential adverse effects, with a particular emphasis on the pros and cons of this shotgun proteomic approach.

Compounds 8 and 24 are the promising candidates for the development of new agents against EV D68 and A71 viruses.