Chemical Probe Synthesis and Chemical Biology
Research within the Hodgkinson group is focused on the synthesis of novel chemical probes and their applications in studying biological processes otherwise challenging to study by genetic approaches alone. We are currently interested in developing chemical probes for class I Histone Deacetylase (HDAC) enzymes and their protein partners that exist within seven distinct class I HDAC multiprotein corepressor complexes. We are in a prime position to achieve this within the Leicester Institute of Structural and Chemical Biology and collaborate with the research groups of Professor John Schwabe and Professor Shaun Cowley in this area. Applications include using our chemical probes to investigate novel protein-protein interactions within HDAC corepressor complexes, and developing heterobifunctional molecules including proteolysis targeting chimeras (PROTACs) for the targeted degradation of class I HDACs and associated partners via the proteasome. Our goal is that our validated chemical probes will reveal new knowledge and biology of the protein of study and aid the discovery of new therapeutics to treat diseases such as cancer. Importantly, we also want our chemical probes to have applications for others in the research community.
Epigenetics and HDAC modulation
Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from lysine in both histone and non-histone proteins. The deacetylation of histones by HDAC’s results in structural modifications to chromatin which subsequently effects gene transcription. HDAC’s are classified into four in classes; I, IIa, IIb, III and IV. Class I HDAC’s exist in large multi-protein corepressor complexes that play important roles in many diseases including neurological disorders, immune disorders and cancer. HDAC’s and their multi-protein complexes have been targeted for inhibitor design as anti-cancer compounds. The pharmacodynamics of particular HDAC inhibitors are hypothesised to be dependent on the specificity of HDAC inhibition. Thus, opportunities are available towards the design and synthesis of isoform and even complex selective chemical probes by differing approaches, not solely by inhibition, but also by other methods in chemical biology such as targeted protein degradation.