The Discovery And Optimisation Of Small-Molecule Inhibitors Of Human 5 '-Tyrosyl Dna Phosphodiesterase (Tdp2).

Topoisomerases (topo) regulate DNA topology by the transient cleavage and re-ligation of DNA during transcription and replication. Topo II poisons such as etoposide can induce abortive DNA strand breaks in which topo II remains covalently bound to a 5’ DNA strand terminus via a phosphotyrosyl linker. Tyrosyl DNA phosphodiesterase 2 (Tdp2, TTRAP, EAPII) is a recently discovered human 5’-tyrosyl DNA phosphodiesterase which repairs this topo-mediated DNA damage, therefore playing a central role in maintaining normal DNA topology in cells. Cellular depletion of Tdp2 has been shown to result in an increased susceptibility and sensitivity to topo II-induced DNA double strand breaks. It has therefore been proposed that selective pharmacological inhibition of Tdp2 may be a novel approach to overcome intrinsic or acquired resistance to topo II targeted drug therapy. To date, no known drug-like inhibitors of Tdp2 have been identified. We have recently reported a robust ‘mix and read’ HTS compatible assay and this was used to screen a diverse chemical library of approximately 92,000 compounds. From this endeavour, 2 distinct hit series have been identified. Following further chemical exploration of the original hit compounds, small molecule inhibitors of Tdp2 with sub-100nM potencies have been identified. This poster will describe our biological and chemical progress in this area, detailing SAR and some lessons learnt during investigation of this target. Citation Format: Allan M. Jordan, Paul Depledge, Nicola Hamilton, James Hitchin, Gemma Hopkins, Laura Maguire, Alison McGonagle, Daniel Mould, Ali Raoof, Mathew Rushbrooke, James Smith, Kate Smilth, Graeme Thomson, Fabrice Turlais, Ian Waddell, Mandy Watson, Donald Ogilvie. The discovery and optimisation of small-molecule inhibitors of human 5’-tyrosyl DNA phosphodiesterase (Tdp2). [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 3324. doi:10.1158/1538-7445.AM2013-3324