Abstract 4534: Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors

Abstract

Abstract Reversible acetylation state of histones determines the existence of the chromatin in either the euchromatin state or the heterochromatin state, which in turn control the accessibility of transcription factors to promoter regions of genes on the chromatin. This reversible acetylation state is regulated by two enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). Imbalance in the expression of these enzymes is associated with many diseases, with equilibrium tilted towards HDAC in tumors. Reversal of the HDAC enzymes to their basal expression level, by small molecule inhibition, has been shown to significantly reduce the growth of tumors and/or completely eliminate them. Currently, there are three (3) FDA approved HDAC inhibitors in the market: vorinostat, FK228 and belinostat (all approved by the FDA for treatment of cutaneous T-cell lymphoma). Although highly effective, these compounds suffer drawbacks such as lack of activity against solid tumors, off-target toxicities, short half-life, and lack of HDAC isoform selectivity. To address some of these challenges, we chose to incorporate a targeting moiety to the head group in the classical vorinostat pharmacophoric model (comprising head group, linker and zinc binding group (ZBG)). We envisaged that selective toxicity towards tumors (hence, reduction in off-target toxicities), may be achieved if the HDAC inhibitor is selectively delivered to tumor cells expressing cyclooxygenase 2 (COX-2) enzyme. COX-2, which catalyzes the conversion of arachidonic acid to prostaglandins, is ubiquitously expressed in a wide range of cancer types and has been exploited to selectively image cancer cells in the past. To achieve this, we designed and synthesized series of hydroxamic acid-based compounds having either celecoxib or indomethacin (COX-2 inhibitors) as the targeting moiety. In addition to these compounds, we made compounds having “biaryl group” as ZBG. Compounds based on this ZBG have been reported to selectively inhibit HDAC isoforms 1&2, both culprits in a wide range of cancer types. Consistent with the reported HDAC isoform selectivity, our “biaryl” ZBG compounds potently and selectively inhibited HDACs 1& 2. Also, our hydroxamic acid-based compounds were better than vorinostat in cell-free assay and showed potent activity in MCF-7, A549 and HCT-116 cancer cell lines. Effort is underway to evaluate the in vivo activity of our lead compounds in animal models. Citation Format: Idris Olawale Raji, Emily Janeira, Fatima Yadudu, Fathi Shaghayegh, James Kornacki, Milan Mrksich, Adegboyega Oyelere. Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2015-4534