Abstract 2519: A class of biometallo-organic compounds that target human topoisomerase IIa

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Abstract Topoisomerase IIa (topo II) is a nuclear enzyme that changes the topological state of DNA by breaking and rejoining the phosphodiester backbone of DNA. It is an important target for anticancer therapy and a number of agents are known to influence its action in vivo. These agents operate by either disrupting the cleavage-resealing cycle (interfacial poisons) or by simply blocking catalytic action of topo II (catalytic inhibitors). A new class of metallo-drugs is described that is unique in acting by both mechanisms. These are a series of fully characterized crystalline d8 coordination compounds with tetradentate ligands that we have evaluated for their targeting potential with topo II. These compounds are quite toxic to cells in culture with inhibitory values in low micromolar range. Mechanistic in vitro data with purified enzyme reveal these compounds to act as both catalytic inhibitors and as interfacial poisons over the same range of drug concentration. For example, CC50 values (drug concentrations yield 50% maximum DNA cleavage) were 3.47 µM for the prototype metallo-agent (compared to 5.47 µM for etoposide). Acting as catalytic inhibitors, the IC50 value was 3.17 µM. In sum, these compounds exhibit dual mechanisms in vitro, by stabilizing the covalent cleavage complex as well as blocking catalytic function. Analysis of endogenous topo II activity in HeLa cells confirms that the compounds target endogenous topo II by stabilizing the covalent cleavage complex and therefore acting as a poison in a cellular context. Endogenous topo I was not affected by the drug showing that these novel metallo-agents are type II specific. The dual mechanism of targeting of topo II suggests significant anti-tumor potential, and further studies are being conducted to evaluate clinical potential. 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 2519. doi:10.1158/1538-7445.AM2011-2519