Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

Self-Association of Nicotinamide in Aqueous-Solution - Nmr-Studies of Nicotinamide and the Mono-Methyl-Substituted and Di-Methyl-Substituted Amide Analogs

The concentration-dependent self-association of nicotinamide in solution has been studied by H-1 and C-13 n.m.r. spectroscopy, attendant relaxation time measurements, and osmometric techniques. N-Methylnicotinamide and N,N-dimethylnicotinamide were also studied to evaluate the role of the amide group in the association process. The osmometric studies indicated that the dimethyl-substituted analogue underwent little (if any) self-association, whereas nicotinamide and N-methylnicotinamide did self-associate. The concentration-dependent H-1 and C-13 chemical shift profiles of nicotinamide and the monosubstituted analogue indicated that the association involved the amide group and did not occur through stacking of the pyridine rings. Spin lattice relaxation (T1) studies indicated that the T1 (ortho C)/T1(para C) ratio of nicotinamide decreased with increasing concentration, and that loss of a preferred axis of rotation had occurred due to formation of a large associated species. The T1 ratios of either substituted amide analogue were not concentration-dependent. The extent of self-association of the monosubstituted derivative was insufficient to affect the measured T1 ratios. These data indicate that the self-association of nicotinamide in aqueous solution occurs primarily through interamide hydrogen bonding