Novel Molecular Templates Targeting Histone Deacetylase 6 - Promising Strategy Towards Clinical Translation
Year: 2022
Type: dissertation
Abstract: Histone deacetylase 6 (HDAC6) is a maverick member of the lysine deacetylase family of proteins collectively known as histone deacetylases (HDACs). HDAC6 is structurally unique with peculiar, non-conserved domains that differentiates it in terms of location and function. Functionally, HDAC6 deacetylates non-histone substrates and regulates protein function, cytoskeletal dynamics, and cell migration. These roles are essential to cellular function and survival and have disease implicating consequences in several cancers and neurodegeneration. Interestingly, loss of HDAC6 function by inhibition, degradation, or deletion is well tolerated and HDAC6-knockout mice develop identically as wildtype mice. These combined attributes have made HDAC6 highly attractive to medicinal chemists and clinicians as an effective therapeutic target. Six ‘HDAC6-selective’ drugs are currently in clinical studies, however, a rational molecular design strategy for selectively inhibiting HDAC6 is not well defined, and several of these inhibitors achieved selectivity stochastically. This thesis describes a rational, iterative, and structural engineering strategy that identified through multiple x-ray crystallography structures, a unique molecular template to reliably target HDA6 selectively. Inspired by this chemical template, newer analogous with picomolar binding affinities and outstanding selectivity for HDAC6 were designed. These new analogues have desirable pharmacokinetic profiles and brain bioavailability, affording their use in the in vivo investigation of HDAC6-relevant diseases such as melanoma, multiple myeloma, and Alzheimer’s disease. Additionally, chimeric degraders of HDAC6 known as PROteolysis TArgeting ChimeraS, PROTACS inspired by initially reported targeted motifs were designed. These HDAC6 PROTACS potently and selectively degraded HDAC6, demonstrating >95% HDAC6 degradation with sub-nanomolar. In conclusion, this thesis encompasses a body of work with significant impact. Firstly, it provides a structural template with a unique binding modality that can be harnessed by medicinal chemists and drug discovery teams interested in the selective targeting of HDAC6. Secondly, the structural engineering strategy described herein can provide a blueprint for optimizing lead HDAC6 candidates for pharmacokinetic improvements and advanced preclinical studies. Finally, developing a HDAC6 degrader technology from this structural template provides a complementary approach that can afford superior efficacy. Collectively, this thesis provides and validates a unique and robust binding modality that can be harnessed by future HDAC6 drug programs.
Source: TSpace (University of Toronto)
Author: Olaoye, Olasunkanmi
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7132963188