Title:Advances in the Design and Development of PROTAC-mediated HDAC
Degradation
Volume: 22
Issue: 5
Author(s): Daniel Alencar Rodrigues*, Andrew Roe, Darren Griffith and Tríona Ní Chonghaile
Affiliation:
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
Keywords:
PROTACs, HDAC, HDAC inhibitors, HDAC degraders, multitarget, IAP.
Abstract: Due to developments in modern chemistry, previously uundruggable substrates are now
targetable thanks to selective degradation using the ubiquitin-proteasomal degradation system.
PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically
to degrade target proteins. They are of significant interest to industry and academia as they
are highly specific and can target previously undruggable target proteins from transcription factors
to enzymes. More than 15 degraders are expected to be evaluated in clinical trials by the end of
2021. Herein, we describe recent advances in the design and development of PROTAC-mediated
degradation of histone deacetylases (HDACs). PROTAC-mediated degradation of HDACs can offer
some significant advantages over direct inhibition, such as the use of substoichiometric doses
and the potential to disrupt enzyme-independent HDAC function. We discuss the potential implication
of the degradation of HDACs in comparison with HDAC knockout studies. Along with the selection
of HDAC inhibitors and E3 ligase ligands for the design of PROTACs. The potential utility
of HDAC PROTACs in various disease pathologies from cancer to inflammation to neurodegeneration
is driving the interest in this field.
