Histone deacetylases (HDACs) and histone acetyltransferases are part of the epigenetic machinery that controls the acetylation state of histones, and important factors in the regulation of cellular processes such as chromatin condensation and gene expression. HDAC6, a Class IIb zinc-dependent HDAC, is structurally and functionally unique. The protein harbors a duplicate catalytic domain, and while most of the 18 mammalian HDACs act in the nucleus, HDAC6 is located predominantly in the cytoplasm and the main responsible for deacetylation of tubulin. In addition, HDAC6 has non-histone substrates like the heat shock protein or cortactin. HDAC6 has been reported to play a role in a plethora of health conditions including a great variety of cancers, inflammatory and autoimmune diseases, pathologies of the nervous system such as Charcot-Marie-Tooth disease, chemotherapy-induced peripheral neuropathy, Alzheimer's disease and mental disorders such as depression. Many available HDAC6-selective inhibitors contain a hydroxamic moiety, a functional group associated with poor PK, multiple off-target interactions and potential mutagenicity. The development of non-hydroxamic HDAC6 inhibitors is desirable. A novel series of HDAC6 inhibitors bearing a 1,2,4-oxadiazole zinc binding group with biochemical potency in the nanomolar range will be presented. Through structure-activity relationship-guided design, several hundreds of compounds have been synthesized to identify preclinical candidates. Selected molecules induce strong acetylation of α-tubulin compared to low acetylation of histones H3 and H4 in MOLP8 and EOL-1 cell lines, confirming their HDAC6 selectivity over class I HDACs. Compounds had favorable pharmacokinetic profiles with high bioavailability and low to moderate clearance, and were deemed suitable for oral administration. These compounds were well tolerated and in vivo target engagement in tissues was demonstrated in MTD studies. Further in vitro and in vivo studies of both compounds are currently in progress.

Discovery of a novel series of selective non-hydroxamic HDAC6 inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.