- Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation
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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 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystallization of 5 with MTH1 revealed the ligand in a φ-cis-N-(pyridin-2-yl)acetamide conformation enabling a key intramolecular hydrogen bond and polar interactions with residues Gly34 and Asp120. Modification of literature compound TH287 with O- and N-linked aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM). Triazolopyridine 32 emerged as a highly selective lead compound with a suitable in vitro 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.
- 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.
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supporting information
p. 358 - 364
(2019/12/02)
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