Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.

Anticancer effects of the MHY218 novel hydroxamic acid-derived histone deacetylase inhibitor in human ovarian cancer cells.

To investigate the anticancer effects of the novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor MHY218, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human ovarian cancer cells. The anticancer effects of MHY218 on cell viability, cell cycle regulation and apoptosis were investigated. In addition, MHY218 or SAHA was administered for 28 days in a tumor carcinomatosis model with SKOV-3 cells. MHY218 significantly reduced the expression of HDAC4 and HDAC7 in SKOV-3 cells. Similarly, MHY218 also inhibited total HDAC, HDAC1, HDAC4 and HDAC7 enzyme activity in a concentration-dependent manner. The anticancer effect of MHY218 (IC50, 3.2 microM) was more potent than SAHA (IC50, 3.9 microM) in suppressing the SKOV-3 cell viability. Moreover, MHY218 markedly increased expression of p21WAF1/CIP1, which acts as a cell cycle inhibitor. Cell cycle analysis showed that the high dose (5 microM) of MHY218 significantly increased the proportion of cells in the G2/M phase. In particular, MHY218 and SAHA significantly increased the sub-G1 population and the number of TUNEL-positive apoptotic cells compared with those in the untreated control. These results were confirmed by analysis of poly-ADP ribose polymerase (PARP), where MHY218 and SAHA increased the level of an 85-kDa fragment resulting from PARP cleavage as well as caspase-3 activity. Likewise, MHY218-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and Bax/Bcl-2 ratio. In an in vivo tumor carcinomatosis model, the growth of transplanted SKOV-3 cells was inhibited by 71% after treatment with MHY218 (10 mg/kg), whereas SAHA (25 mg/kg) suppressed growth by 48%. These results indicate that MHY218 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in ovarian cancer chemotherapy, warranting further investigation.