A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders

Abstract Proteolysis-targeting chimera (PROTAC) technology has emerged as a powerful therapeutic strategy in drug discovery. Conventional PROACs are heterobifunctional molecules composed of two distinct ligands that independently bind to a protein of interest (POI) and an E3 ligase. However, their inherently large molecular size often leads to suboptimal drug-like properties. In this study, we report a “2-in-1” PROTAC design strategy for developing more compact HDAC8 degraders by integrating the CRBN-recruiting ligand into the capping group of an HDAC8 warhead, thereby enabling a single structural motif to engage both HDAC8 and CRBN. Compared to our first generation HDAC8 degrader YX862, the new degraders exhibit improved selectivity, reduced molecular weight, improved overall drug-like properties, and, importantly, potent HDAC8 degradation in vivo. These findings highlight the therapeutic potential of this new class of HDAC8 degraders, and demonstrate a conceptual framework for integrating E3 ligase recruitment and target engagement into a more efficient and compact PROTAC design.