Paradigm shift of "classical" HDAC inhibitors to "hybrid" HDAC inhibitors in therapeutic interventions

Abstract

'Epigenetic' regulation of genes via post-translational modulation of proteins is the current mainstay approach for the disease therapies, particularly explored in the Histone Deacetylase (HDAC) class of enzymes. Mainly sight saw in cancer chemotherapeutics, HDAC inhibitors have also found a promising role in other diseases (neurodegenerative disorders, cardiovascular diseases, and viral infections) and successfully entered in various combination therapies (pre-clinical/clinical stages). The prevalent flexibility in the structural design of HDAC inhibitors makes them easily tuneable to merge with other pharmacophore modules for generating multi-targeted single hybrids as a novel tactic to overcome drawbacks of polypharmacy. Herein, we reviewed the putative role of prevalent HDAC hybrids inhibitors in the current and prospective stage as a translational approach to overcome the limitations of the existing conventional drug candidates (parent molecule) when used either alone (drug resistance, solubility issues, adverse side effects, selectivity profile) or in combination (pharmacokinetic interactions, patient compliance) for treating various diseases.

Keywords: Anti-cancer agents; Cardiovascular diseases; Combination therapy; HDAC hybrids; Histone deacetylase; Inhibitors; Neurodegenerative disorders.