Biological Evaluation of Selective Histone Deacetylase 6 Inhibitors and Degraders
Year: 2022
Type: dissertation
Abstract: Histones are key proteins involved in the arrangement of DNA and their interactions can dictate protein expression via post-translational modifications like acetylation. Histone Deacetylases (HDACs) remove acetyl groups from histones and other substrates. Irregular activity of HDACs can lead to various cancers and neurological diseases prompting the development of HDAC inhibitors (HDACi). FDA approved HDAC drugs are unselective, displaying undesirable adverse effects. Therefore, novel selective HDAC6i were investigated for their potential to treat multiple neoplasia. The developed inhibitors demonstrated selectivity for HDAC6, several fold greater than clinical candidate, citarinostat. Target engagement was achieved in the nM-µM concentration range and induced cytotoxicity in a variety of cell lines. Furthermore, proteolysis targeting chimeras (PROTACs) were explored to achieve degradation of cellular HDAC6. The developed PROTACs exhibited selective degradation of HDAC6 in the nM concentration range in multiple myeloma cells. Overall, this thesis investigates the potential for HDAC6-selective molecules and their therapeutic value.
Source: TSpace (University of Toronto)
Author: Garcha, Harsimran Kaur
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7133076037