ACS Medicinal Chemistry Letters p. 358 - 364 (2020)
Update date:2022-08-04
Topics:
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.
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.
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