biostudies-literatureTahara YKAlexander von Humboldt-StiftungNational Cancer InstituteNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS2606-2615https://www.ebi.ac.uk/biostudies/studies/S-EPMC7061906biostudies-literatureUnknown14(12)Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of small-molecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound <b>5</b> (SU0383) with IC₅₀(NUDT1) = 0.034 μM and ICACS chemical biologyDual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1.PMC7061906R01 GM110050R01 CA217809P30 CA124435CA217809R01 GM067201GM067201GM110050Hebenbrock MKool ETKietrys AMTahara YKWilson DLLee YfalseDual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1.Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of small-molecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound <b>5</b> (SU0383) with IC₅₀(NUDT1) = 0.034 μM and IC2019-01-01T00:00:00Z2019 Dec2026-04-16T21:09:07.203Z2020-10-29T14:22:46ZS-EPMC70619063162255310.1021/acschembio.9b00490