Title: Nonpeptide Macrocyclic Histone Deacetylase Inhibitors for Targeted Cancer Treatment
Abstract: Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. HDAC inhibitors hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. However, most of these agents are non-selective inhibitors of all HDAC isoforms; and a large number of the identified HDAC inhibitors have not progressed beyond preclinical characterizations. Of the several structurally distinct small molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDAC inhibitors. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDAC inhibitors known to date comprise of complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Therefore, if there is no significant paradigm shift in the current molecular design approaches, the vast therapeutic potentials of HDAC inhibition may remained largely untapped. Toward improving the therapeutic indices of current HDAC inhibitors, my lab is developing novel approaches for organ-selective delivery of HDAC inhibitors for potential use in targeted lung cancer therapy applications. In this presentation, I will discuss the discovery and SAR studies of a new class of macrocyclic HDAC inhibitors based on the macrolide antibiotics skeletons. I will also present preliminary evidence for lung selective accumulation of selected examples of this new class of HDAC inhibitors. In general, the prospect of tissue-selective HDAC inhibition is a particularly enticing alternative to isoform selective inhibition and could lead to the identification of new chemotherapeutic agents with broad application in targeted cancer therapy.