Abstract 1010: New thiol-ω(γ-lactam amide) SAHA analogues as potent histone deacetylase (HDAC) inhibitors..

Abstract

Abstract Histone deacetylase inhibitors (HDACi) are one of the last frontiers in pharmaceutical research. Two HDACi are already part of armamentarium of the anticancer drugs of the oncologists: Vorinostat, Zolinza® (SAHA) and Romidepsin, Istodax® (depsipeptide; FK-228), both licensed by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Beyond them, more than twenty new drugs are currently under pre-clinical and clinical investigation as single agent and in combination therapies against different cancers and in other several novel therapeutic indications. Mainly they are hydroxamic acids and benzamide derivatives; however none has emerged superior to SAHA in terms of potency. In our search, we have selected a new generation of HDACi: thiol-based SAHA bearing a lactam amide in ω-position. This new generation was highly competitive compared to competing drugs, displaying sub-micromolar to low nanomolar inhibitor activity on HDACs, being especially powerful on HDAC6 isoform. They exhibited higher anti-proliferative activity than SAHA on different human cell lines. In vivo they were orally administered and showed a higher potency than SAHA, with a negligible toxicity. The overall profile of this new class of HDAC inhibitors, including synthesis and a comprehensive pharmacological characterization, will be presented. These encouraging results prompted us to select a drug candidate which is currently in a phase of pre-clinical evaluation. Citation Format: Giuseppe Giannini, Gianfranco Battistuzzi, Davide Vignola, Loredana Vesci, Ferdinando Maria Milazzo, Mario Berardino Guglielmi, Marcella Barbarino, Claudio Pisano, Walter Cabri. New thiol-ω(γ-lactam amide) SAHA analogues as potent histone deacetylase (HDAC) inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1010. doi:10.1158/1538-7445.AM2013-1010