A pan-HDAC chemoproteomics assay to profile drugs
Le résumé fourni par la source
As some histone deacetylases (HDAC) hold key epigenetic roles, several HDAC inhibitors have already been approved for clinical use. Indeed, dysregulation of HDACs’ activity leads to various pathological disorders (cancer, neurodegenerative diseases). However, the substrates of the 11 zinc-dependent HDACs are not necessarily histones, not even always proteins, and act on various post-translational acylations, sometimes with poor deacetylation activity. Understanding the biological functions and substrates of each HDAC is a major focus of ongoing research, where chemical probes discovery and chemoproteomics have a central role. Chemoproteomic approaches, like affinity-based protein profiling (AfBPP), have transformed drug target identification through the combination of small-molecule affinity probes and sensitive LC-MS/MS detection. While our team’s previous efforts successfully mapped global inhibitor profiles across 9 HDACs and uncovered surprising off-targets of HDAC drugs [1,2], critical gaps remain in isoform-resolved datasets - with HDAC9 and HDAC11 remaining elusive. Therefore, we are developing a next-generation chemoproteomic platform for pan-HDAC drug profiling. We have synthesized and tested new hydroxamate affinity probes to address the entire zinc-dependent HDAC family. Additionally, we are evaluating these molecules in different biological materials, including mouse brain and diverse human cancer cell lines, which feature various HDAC expression profiles. We particularly focus on HDAC9 and HDAC11, whose general low expression has rendered chemoproteomics analysis out of reach. With our improved assay, this research will further our understanding of the applications of HDAC inhibitors, reveal new interaction partners, and contribute to improving chemical probes and drug design. A pan-HDAC chemoproteomics assay would provide two key benefits. It would allow us to re-evaluate the actual selectivity of commonly used inhibitors. And, most importantly, it would allow us to investigate under-studied HDAC9 and HDAC11, by enhancing their enrichment and quantification in complex samples, enabling drug repurposing. Altogether, this work advances high- resolution chemoproteomic mapping of HDAC-inhibitor interactions.
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