The development of ligands that as single chemical entities are able to modulate multiple epigenetic targets simultaneously (designed epigenetic multiple ligands) is still in its infancy. We are witnessing some advances with combinations of the fused or linked pharmacophores of an epi-drug and other anticancer agents. More recently, however, a very promising approach has been developed in which a single chemical entity exerts several therapeutic activities simultaneously, such as a compound that inhibits several epigenetic enzymes and as a consequence displays multiple biological profiles that address synergistically a particular multifactorial disease. Despite their promiscuity, these multiple epigenetic ligands have exciting conceptual advantages, as they (i) lower the risk of drug-drug interactions compared to cocktails or multicomponent drugs and facilitate ADMET and toxicology studies, (ii) minimize the development of drug resistance, (iii) exploit synergies between the targeted pathways/factors and (iv) can generally be used at lower therapeutically effective concentrations than the single target drugs. The obvious problem with such compounds is to find/design drugs which target multiple effectors with high selectivity and efficiency without displaying extensive off-target effects. In addition, the rational design of multiple epi-ligands is a major challenge. In this review we provide structurally-based principles and the optimization of activities towards the different epigenetic targets.
Keywords: Epigenetics, cancer, chromatin, histones, DNA, enzyme inhibitors, multiple ligands, therapeutic activities, epigenetic multiple ligands, exploit synergies, neurodevelopmentalmalformations, concordant structural, amino acids, embryonal tumors, hydrophobic
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