Cell biologist’s perspective: frontiers in the development of PROTAC-HDAC degraders

Abstract

This “Minireview and Perspective” article describes histone deacetylases (HDACs), as promising specific molecular targets to treat a variety of disease states by downregulating the expression of associated proteins with the use of a new generation of bioengineered compounds called protein targeting chimeras (PROTACs). We present the classification of HDACs, discuss their functions as key epigenetic regulators of gene expression, describe their roles in the biology of aging, describe histone- and nonhistone substrates of HDACs and their functions, and briefly introduce the concept of histone-modifying multiprotein complexes. Insight into the biological functions of specific HDACs comes from genetic knockout studies of individual genes encoding deacetylases. Initially discovered and newly developed HDAC inhibitors are powerful tools to investigate the functions of HDACs in cells and organs, that have also been successfully used in numerous preclinical and clinical studies, as promising drug candidates. We focus on the molecular and cellular mechanisms of their action, and introduce PROTACs, which are bivalent degrader molecules that have been recently developed to target HDACs. We then discuss recent studies focused on designing and testing several classes of selective and nonselective HDAC degraders in terms of their molecular and cellular mechanisms of action. Finally, we present open questions and new perspectives in developing the next generation of HDAC-degraders.