Histone deacetylases (HDACs) are promising targets of novel cancer therapeutic agents. Previous screening efforts have identified several classes of HDAC inhibitors, most notably of zinc chelator variety (i.e., hydroxamic acids, ortho-amino anilides, etc.).
In this research we describe a group of novel class II HDAC suicide inhibitors that were synthesized through microwave-assisted Petasis and Mannich reactions. The mechanism of action of these compounds has been shown to involve initial chelation of a Lewis acidic zinc(II) ions, which then catalyzes decomposition of compounds to reactive quinone methide (QM) intermediates. The QM intermediates are subsequently covalently trapped by a nearby nucleophilic thiol side chain of a cysteine residue. Stability of these compounds in the presence of various Lewis acids was tested in the production of QM intermediates.
Biochemical assays have been performed to determine the compounds’ inhibitory activity against HDACs. A selected few have shown IC50 values in the nanomolar range for class II HDACs, all of which share similar structural features. Protein mass spectrometry confirmed the covalent binding of these mechanism-based inhibitors. Cytotoxicity of the compounds was determined by a cell-viability assay. We have demonstrated that QM precursors serve as a new class of potential small-molecule mechanism-based HDAC inhibitors that could be used to further study the relationship between
PROJECT: Covalent Inhibition of Histone Deacetylases via in situ-Generated Quinone Methides
An internship at the Broad is a unique and irreplaceable learning experience. The SRPG program has allowed me to interact with creative and inspirational mentors who are extremely passionate about their research. Their ambitious approach to complex problems is reflected in the meaningful research I was able to take part in this summer.