Abstract 689: Identification and optimization of novel chemical matter via a structure-based approach resulting in a probe for MTH1

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Abstract Cancer cells can form reactive oxygen species (ROS) due to altered redox regulation that affect desoxynucleosides triphosphates (dNTP) in particular. 8-oxo-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP) and 2-hydroxydeoxyadenosine-5'-triphosphate (2-OH-dATP) are the two most abundant oxidative nucleotide lesions in this respect. These undesired nucleoside triphosphates are sanitized by the hydrolase MTH1 (also known as NUDT1) in order to prevent their incorporation into replicating DNA. Sprint Bioscience created a series of drug-like, potent and selective MTH1 inhibitors using fragment-based drug discovery methods. In collaboration with Bayer, these inhibitors were extensively profiled, both in vitro and in vivo, to allow for the selection of a probe molecule with attractive properties for in vivo target validation studies. Herein, we would like to share novel chemical matter and it's binding to MTH1 in protein co-crystal structures. Furthermore, we describe the consecutive, stepwise structure-based optimization process. Extensive SAR elaboration clearly revealed the essential moieties for high potency and favorable ADME properties. We are able to report for the first time how we identified BAY-707 as a very potent and highly selective MTH1 inhibitor representing a potential probe to further evaluate the scope and limitations of MTH1 inhibition for therapeutic applications. Citation Format: Marcus Bauser, Anja Giese, Manuel Ellermann, Judith Guenther, Ashley Eheim, Stefanie Bunse, Roland Neuhaus, Joerg Weiske, Maria Quanz, Andrea Glasauer, Katrin Nowak-Reppel, Benjamin Bader, Horst Irlbacher, Hanna Meyer, Nina Queisser, Andrea Haegebarth, Matyas Gorjanacz, Lionel Tresaugues, Tobias Ginman, Fredrik Rahm, Martin Andersson, Ulrica Ericsson, Rickard Forsblom, Johan Lindstroem, Camilla Silvander, Jenny Vicklund. Identification and optimization of novel chemical matter via a structure-based approach resulting in a probe for MTH1 [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 689.

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