Farand, Julie Kropf, Jeffrey E. Blomgren, Peter Xu, Jianjun Schmitt, Aaron C. Newby, Zachary E. Wang, Ting Murakami, Eisuke Barauskas, Ona Sudhamsu, Jawahar Feng, Joy Y. Niedziela-Majka, Anita Schultz, Brian E. Schwartz, Karen Viatchenko-Karpinski, Serge Kornyeyev, Dmytro Kashishian, Adam Fan, Peidong Chen, Xiaowu Lansdon, Eric B. Ports, Michael O. Currie, Kevin S. Watkins, William J. Notte, Gregory T. Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)­validation. Tetrahydronaphthyridine <b>5</b> was rapidly identified as a highly potent MTH1 inhibitor (IC<sub>50</sub> = 0.043 nM). Cocrystallization of <b>5</b> with MTH1 revealed the ligand in a Φ-<i>cis</i>-<i>N</i>-(pyridin-2-yl)­acetamide conformation enabling a key intramolecular hydrogen bond and polar interactions with residues Gly34 and Asp120. Modification of literature compound <b>TH287</b> with <i>O</i>- and <i>N</i>-linked aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine <b>25</b> (IC<sub>50</sub> = 0.49 nM). Triazolopyridine <b>32</b> emerged as a highly selective lead compound with a suitable <i>in vitro</i> profile and desirable pharmacokinetic properties in rat. Elucidation of the DNA damage response, cell viability, and intracellular concentrations of oxo-NTPs (oxidized nucleoside triphosphates) as a function of MTH1 knockdown and/or small molecule inhibition was studied. Based on our findings, we were unable to provide evidence to further pursue MTH1 as an oncology target. Selective MTH 1 Inhibitors;Asp 120. Modification;alkyl aryl substituents;Enabling Rapid Target;MTH 1 inhibitor;oncology target;MTH 1 inhibitors;MTH 1 knockdown;MTH 1;Φ-;residues Gly 34;DNA damage response;intramolecular hydrogen bond;IC 50;literature compound TH 287 2019-11-18
    https://acs.figshare.com/articles/journal_contribution/Discovery_of_Potent_and_Selective_MTH1_Inhibitors_for_Oncology_Enabling_Rapid_Target_In_Validation/10325072
10.1021/acsmedchemlett.9b00420.s001