Existing cancer drugs that block entire families of histone deacetylase (HDAC) enzymes cause severe side effects because they cannot distinguish between the seven distinct protein complexes these enzymes form inside cells. This project aims to build molecular tools—called PROTACs—that selectively destroy only one HDAC-containing complex at a time, leaving the others untouched. The problem is clear: the four FDA-approved HDAC inhibitors all hit multiple HDAC complexes at once, triggering toxicities that limit their use, especially against solid tumours. Researchers suspect that targeting individual HDAC complexes, rather than the enzymes broadly, could yield more effective drugs with fewer side effects. But no tools exist to test this idea cleanly. The team will synthesise libraries of PROTACs, each designed to recruit a degradation enzyme to a specific HDAC complex based on the complex’s unique 3D structure. They will then test each PROTAC’s selectivity in cancer cells and use gene and protein analysis to confirm they are hitting only the intended target. If successful, the project will deliver validated chemical probes for academic labs studying HDAC complexes in cancer and other diseases, and lead compounds for pharmaceutical companies developing next-generation HDAC-targeting therapies.
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Histone Deacetylases (HDACs) are essential enzymes in the regulation of chromatin structure and gene transcription. FDA approved HDAC inhibitors, such as vorinsotat, perturb the transcription of genes involved in cell cycle regulation, DNA damage repair, apoptosis pathways and transcriptional regulation, leading to compromised cell viability in cancer cells. However, since the FDA approval of vorinsotat in 2006, only three additional HDAC inhibitors have gained FDA approval, all of which are pan-HDAC inhibitors. The side effects experienced by patients taking pan-HDAC inhibitors can be severe, while dose-limiting toxicities render these drugs ineffective for the treatment of solid tumours. Many researchers believe that the selective targeting of individual HDAC isoforms will aid the discovery of more efficacious HDAC targeting therapeutics while dialling out the undesired side effects exhibited with FDA approved pan-HDAC inhibitors. However, importantly, HDAC1, HDAC2 and HDAC3, exist in vivo in 7 distinct corepressor complexes, and we propose that the targeting of individual HDAC1-3 containing corepressor complexes will be important for the future discovery of truly targeted HDAC therapeutics tailored for specific diseases. We have pioneered the use of proteolysis targeting chimeras (PROTACs) that target HDAC1-3 for degradation. To date, just over 20 PROTACs have reached clinical trials for oncology drug targets. The mechanism by which PROTACs degrade HDAC1-3 offers an exciting opportunity to target not only the HDAC enzyme but also the HDAC corepressor complex. Degradation by PROTACs is driven by the establishment of a ternary assembly between the PROTAC, HDAC corepressor complex and an E3-ligase required for degradation. Based on structural data, these ternary assemblies will be different between different corepressor complexes allowing us to induce the degradation in a complex-specific manner. In this proposal, we will pursue three objectives. Objective 1 involves the synthesis of PROTAC libraries with differing chemical modifications to recruit the E3-ligase to the HDAC corepressor complex in differing spatial orientations. Since the assembly of each HDAC-corepressor complex is structurally unique, the variation in the linker and E3-ligase attachment will cause the PROTAC to interact with each of the 7 complexes differently, thus leading to complex selective degraders. In objective 2, we will determine the selectivity of each PROTAC for individual HDAC corepressor complexes in vitro and corepressor complex degradation in cancer cells. In objective 3, we will use transcriptomics and proteomics to confirm the selectivity of HDAC corepressor complex targets, and optimise PROTACs as lead compounds for drug discovery. This will not only provide valuable chemical tools for the target validation of individual HDAC corepressor complexes in cancer models but also generate lead compounds for the drug discovery of new HDAC targeting therapeutics. This project will directly benefit researchers in the life sciences and medical sciences who want to validate the role of individual HDAC corepressor complexes as potential drug targets in their cancer of study and potentially other diseases. The lead PROTAC compounds generated will also be of interest to those in biotech and pharmaceutical industries working in drug development. In the longer term, we expect this research will lead to the discovery of new and improved HDAC targeting therapeutics for cancer patients.
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