Histone deacetylases (HDACs) are known to be a significant enzyme of epigenetic regulations and they are a well�known therapeutic target for cancer. Human HDAC enzymes have 11 isoforms and most of them are zinc-dependent enzymes which play the roles of proliferation, de-differentiation and anti-apoptosis in cancer cells. We reprted on d-lactam and ?-lactam based HDAC inhibitors. They showed high activity in in vitro HDAC inhibitory assays and cancer cell growth inhibitory assays. Most of them, however displayed low metabolic stability in mouse liver microsomes mainly due to the NIH shift or hydrolysis of hydroxamic acid moiety. So, we introduced a conjugation system by replacing lactam with pyridone of core group, which places conjugated double bonds between the pyridone core and hydroxamic acid . Consequently, Most of pyridone based HDAC inhibitors showed similar or better HDAC enzyme inhibitory activity, and metabolic stability. A1399 proved to be especially powerful as HDAC inhibitors, because of the highest rate of activity in in vitro HDAC enzyme inhibitory, cancer cell growth inhibitory assays and having potent selectivity to HDAC1 and HDAC6.

Discovery of pyridone based HDAC inhibitors for metabolic stability

244th National Meeting (2012)

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