biostudies-literatureWaaler JAcademy of FinlandSouth-Eastern Norway Regional Health AuthorityKreftforeningenNorges Forskningsr?dJane ja Aatos Erkon S??ti?Sigrid Jus?liuksen S??ti?Universitetet i Oslo6834-6846https://www.ebi.ac.uk/biostudies/studies/S-EPMC8008393biostudies-literatureUnknown63(13)Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and <i>trans-</i>cyclobutyl linker of the lead compound <b>1</b> were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC₅₀ inhibition in WNT/β<i>-</i>catenin signaling cellular reporter assay. The Journal of medicinal chemistryPreclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.PMC80083935803958319299201501216/00528-915/00779-22626132962262019090267639287063294085Murthy SDamen ELycke MKrauss SWaaler JLeenders RGGNazare MWegert ALehtio LSowa STGalera-Prat AAlam Brinch SNieczypor PAertssen SfalsePreclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and <i>trans-</i>cyclobutyl linker of the lead compound <b>1</b> were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC₅₀ inhibition in WNT/β<i>-</i>catenin signaling cellular reporter assay. The 2020-01-01T00:00:00Z2020 Jul2026-05-02T00:34:11.413Z2022-02-09T13:21:01.669ZS-EPMC80083933251191710.1021/acs.jmedchem.0c00208