Abstract
Abstract M3541 is an ATP-competitive inhibitor of the Ataxia telangiectasia mutated (ATM) kinase (IC50 < 1 nM), which targets tumor cell survival and growth by inhibiting double-strand break (DSB) repair as well as checkpoint control. DSB repair is crucial for survival of malignant tumor cells, especially under treatment with DNA damaging chemo- and radiotherapy. As such, the rationale of pharmacological inhibition of ATM is to increase and maintain the extent of unrepaired DNA damage generated by radio-, chemotherapy, and targeted therapies to drive tumor cells into cell death. We have developed an orally administered, sub-nanomolar potent & selective kinase inhibitor of ATM, M3541, for cancer therapy in combination with DNA damaging modalities. Here, we present the optimization of initial hit matter & its structure-activity relationships leading to our clinical candidate M3541, its chemical structure (first-time disclosure) & preclinical characterization using biochemical, cellular & human tumor xenograft models. M3541 sensitizes tumor cell lines to radiation therapy in vitro and strongly enhances the anti-tumor activity of ionizing radiation in vivo. These effects are due to the inhibition of ATM kinase activity as demonstrated by the levels of the phosphorylation of its primary downstream target CHK2 in human tumor cell lines. M3541 is currently being investigated in a multicenter Ph I clinical trial. Citation Format: Thomas Fuchss, Werner W. Mederski, Frank T. Zenke, Heike Dahmen, Astrid Zimmermann, Andree Blaukat. Highly potent and selective ATM kinase inhibitor M3541: A clinical candidate drug with strong antitumor activity in combination with radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 329.
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