Abstract
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.
Highlights
Challenges for rational epigenetic drug polypharmacology The new paradigm of single chemical entities that antagonize multiple biochemically distinct targets to overcome conventional single-target therapeutics is being pursued in the epigenetic field, in particular for the treatment of cancer [11, 12]
Since some of the epigenetic enzymes such as sirtuins (SIRTs), protein arginine methyltransferases (PRMTs), DNA methyltransferases (DNMTs), and lysine methyltransferases (KMTs) use the same cofactor or cofactors containing adenosine, modulators of several of these enzymes that bind to the corresponding adenosine pockets can be designed, and these might crossreact with related receptors such as kinases
A recent survey, for example, found that over 40 % of drugs according to the Anatomical Therapeutic Chemical (ATC) classification had a reported IC50 < 10 μM for six or more targets [128]
Summary
Principles of polypharmacology Notwithstanding the success of combination therapy, the use of a single drug that modulates several targets might be therapeutically advantageous over the use of drugs in combination. Among the advantages of multitarget drugs vs drug combinations are the more predictable pharmacokinetic (PK) and pharmacodynamic (PD) relationship of the components of a single medicine, the possibility that one motif might improve the bioavailability of the second entity, the greater efficacy against advanced-stage diseases, the lower toxicities, the simultaneous presence of the chemical entities in multiple tissues, and the improved patient compliance [2] To benefit from those effects, it is required that the multitarget drug exhibit balanced in vitro and in vivo activities to match potency for the corresponding targets, as well as optimized PK and safety profiles. Multitarget drugs exhibiting polypharmacology due to their ability to modulate as single chemical entities multiple targets simultaneously are termed multiple ligands [5] and hybrid molecules [6] These molecules should not be considered as pro-drugs, which are those designed to correct the pharmacokinetic and pharmacodynamic profiles of a valuable lead. According to the mechanism of action, hybrid molecules can be classified in three different categories: (a) both entities interact with the same target (“double sword” molecules); (b) both entities independently interact with two different and nonrelated targets; (c) both entities interact simultaneously with two related targets at the same time [6]
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