Back to Search
Start Over
Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 Nov 19; Vol. 11 (3), pp. 358-364. Date of Electronic Publication: 2019 Nov 19 (Print Publication: 2020). - Publication Year :
- 2019
-
Abstract
- 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 (IC <subscript>50</subscript> = 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 (IC <subscript>50</subscript> = 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.<br />Competing Interests: The authors declare no competing financial interest.<br /> (Copyright © 2019 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 11
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 32184970
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.9b00420