Abstract
Abstract Physical or chemical agents that damage DNA such as ionizing radiation are among the most widely used classes of cancer therapeutics today. Double strand breaks (dsb) generated in DNA by radiation induce a multitude of cellular responses, including DNA repair, cell cycle arrest or cell death once the damage is left unrepaired. A complex set of molecular events are responsible for DNA repair mediated by two major repair mechanisms - homologous recombination (HR) or non-homologous end joining (NHEJ). DNA-PKcs together with its regulatory protein subunits Ku70 & Ku80, is an integral component of the NHEJ process and considered an attractive intervention point to inhibit DNA dsb repair. We have developed an orally bioavailable, highly potent & selective inhibitor of DNA-PK, M3814, for cancer therapy in combination with DNA damaging modalities such as radiation & radio-chemotherapy. Here, we present the optimization of initial hit matter & its structure-activity relationships leading to M3814, its chemical structure (first-time disclosure) & preclinical characterization using biochemical, cellular & human tumor xenograft models. M3814 sensitized multiple tumor cell lines to radiation therapy in vitro and strongly enhanced the anti-tumor activity of ionizing radiation in vivo with complete tumor regression by applying a clinically relevant fractionated radiation regimen. These effects are due to inhibition of DNA-PK protein kinase activity as demonstrated by the levels of DNA-PK autophosphorylation in human tumor cell lines & xenograft tumors. M3814 is currently being investigated in PhI/II clinical trials. Citation Format: Thomas Fuchss, Werner W. Mederski, Ulrich Emde, Hans-Peter Buchstallter, Frank Zenke, Astrid Zimmermann, Christian Sirrenberg, Lubo Vassilev, Lars Damstrup, Klaus Urbahns, Andree Blaukat. Highly potent and selective DNA-PK inhibitor M3814 with sustainable anti-tumor activity in combination with radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4198. doi:10.1158/1538-7445.AM2017-4198
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