Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation
Year: 2026
Type: preprint
Abstract: This work reports on a series of von Hippel-Lindau (VHL)-recruiting histone deacetylase 6 (HDAC6) PROTACs based on a vorinostat-inspired HDAC inhibitor. Systematic variations of the VHL ligand, the exit vector, and the linker architecture revealed that longer, semi-rigid linkers promoted efficient HDAC6 degradation. Compounds 12-15 emerged as potent HDAC6 degraders, with 15 exhibiting a half-maximal degradation value of 26 nM with 12 showing particularly rapid degradation kinetics. The lead compounds induced pronounced and preferential HDAC6 degradation in MM.1S and FLT3-ITD-positive MV4-11 cells. Notably, 13-15 displayed submicromolar antiproliferative activity in MV4-11 cells and significantly induced apoptosis. Compound 13 was markedly more active than its non-degrading control nc-13, despite nearly identical HDAC1 and HDAC6 inhibitory activities, which underscores the important contribution of targeted HDAC degradation to the antiproliferative activity. Overall, this study supports VHL-mediated targeted degradation as a promising strategy to translate HDAC6 targeting into pronounced antileukemic activity.
Source: ChemRxiv
Institution: University of Bonn
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221565460