Trials with ‘epigenetic’ drugs: An update

Abstract

Epigenetic inactivation of pivotal genes involved in correct cell growth is a hallmark of human pathologies, in particular cancer. These epigenetic mechanisms, including crosstalk between DNA methylation, histone modifications and non-coding RNAs, affect gene expression and are associated with disease progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. Re-expression of genes epigenetically inactivated can result in the suppression of disease state or sensitization to specific therapies. Small molecules that reverse epigenetic inactivation, so-called epi-drugs, are now undergoing clinical trials. Accordingly, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment have approved some of these drugs.Here, we focus on the biological features of epigenetic molecules, analyzing the mechanism(s) of action and their current use in clinical practice.

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

“…Natural molecules (psammaplins) and rationally designed small molecules (RG108) are sound alternative approaches to modify DNA methylation. RG108 is an exciting drug because it has demethylating activity in vitro and in vivo in non-neuronal systems, and low toxicity-even at high concentrations [120]. We have shown the demethylating efficacy of RG108 in neuronal systems and its robust neuroprotective actions in cell and animal models of motor neuron degeneration [70], thus establishing aberrant DNA methylation as a new disease target in ALS and RG108 as a potential therapy.…”

“…If our hypothesis is correct regarding DNA methylation as a mechanism of disease in ALS, then new avenues for epigenetic therapeutics become available to ALS patients for testing in clinical trials (Table 1). DNA methylation can be modified pharmacologically, and by lifestyle intervention and rehabilitation programs [29,120,121]. Nucleoside analogs and Dnmt inhibitors are available (Table 1) to achieve DNA demethylation, and some DNA methylation modifying drugs are FDA-approved for human use.…”

“…Nucleoside analogs and Dnmt inhibitors are available (Table 1) to achieve DNA demethylation, and some DNA methylation modifying drugs are FDA-approved for human use. Nucleoside analogs are used widely as suicide inhibitors of Dnmts in treating neoplasia, but have dose-limiting toxicity and carcinogenic side effects [29,120]. Blocking the catalytic activity of Dnmts with small molecules is another strategy.…”

“…Blocking the catalytic activity of Dnmts with small molecules is another strategy. Procainamide and hydralazine are FDA-approved for the treatment of cardiac arrhythmia and hypertension owing to their sodium channel blocking activity and cyclic guanosine monophosphate modulation actions, respectively; however, they are now being tested as Dnmt inhibitiors in preclinical studies [120]. In addition to other actions, these drugs can bind CpG-rich sequences and act as partial competitive inhibitors of Dnmt1.…”

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

“…Based on their potent anti-cancer effects, numerous HDACi are currently being tested in various human clinical trials. 2,3 Four HDACi-Suberoylanilide hydroxamic acid (SAHA, Vorinostat), Romidepsin (Depsipeptide, FK228, Istodax), Belinostat (PXD101, Beleodaq) and Panobinostat (LBH589, Farydak)-were US FDAapproved for the treatment of refractory or relapsed cutaneous T-cell lymphoma (CTCL), 4 peripheral T-cell lymphoma (PTCL) 5,6 and multiple myeloma, 7 validating the concept of HDAC inhibition to treat cancer patients.…”