Abstract 2824: PENAO: A small molecule tumor metabolism inhibitor

Abstract

Tumors reorganize the metabolic steps used by normal tissues for glucose utilization and ATP production. Normal tissues rely heavily on oxidative phosphorylation for ATP, while tumor cells employ a route that includes a much greater dependency on glycolysis. This aberrant metabolism allows for tumor survival when oxygen is limiting while providing a mechanism to poison the extracellular environment with acid, which facilitates invasion and metastasis. In particular, tumors harness a crucial enzyme, hexokinase II (HKII), to entrap and channel glucose toward glycolysis. HKII is bound to mitochondria via interaction with the voltage dependent anion channel (VDAC). This affords HKII preferential access to the mitochondrial ATP via inner-membrane adenine nucleotide translocase (ANT) to rapidly phosphorylate and trap the incoming glucose, effectively initiating and regulating the glycolytic flux across the tumor cytosol. We have developed a novel covalent inhibitor of ANT called PENAO, (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) (1). This molecule blocks ANT delivery of ATP to VDAC-bound HKII, thus inhibiting tumor cell metabolism, and triggers the mitochondrial permeability transition pore, resulting in proliferation arrest and apoptotic cell death. PENAO rapidly enters the cell via an organic ion transporter and reacts with Cys160 and Cys257 on the matrix face of ANT, which leads to arrest of proliferation of the cell and then apoptosis. PENAO targets both proliferating endothelial and tumor cells. It is very well tolerated in mice and has potent anti-tumor activity in murine tumor models when administered either subcutaneously or intravenously. PENAO is the most potent anti-tumor compound of its type so far reported and will enter a Phase I/IIa clinical trial in adults with solid tumors refractory to standard therapy in 2011. 1. Dilda PJ, Decollogne S, Weerakoon L, et al. Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. J Med Chem 2009;52(20):6209-16. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2824. doi:10.1158/1538-7445.AM2011-2824