Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation
- 1Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, Germany, 53121
- 2Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, Germany, 53121
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.
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BibTeX
@misc{miranda2026solidphase,
title = {{Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation}},
author = {Martina Miranda and Maria Hanl and Nisha Setia and Sophie Spülbeck and Katrin Nekipelov and Helena Skalski and Hadi Alizadeh and David Oppermann and Gerd Bendas and Michael Gütschow and Finn K. Hansen},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010272/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010272/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation
AU - Martina Miranda
AU - Maria Hanl
AU - Nisha Setia
AU - Sophie Spülbeck
AU - Katrin Nekipelov
AU - Helena Skalski
AU - Hadi Alizadeh
AU - David Oppermann
AU - Gerd Bendas
AU - Michael Gütschow
AU - Finn K. Hansen
PY - 2026
DA - 2026/10/12
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010272/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010272/v1
AB - 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.
ER -