Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor
Waaler, Jo; Leenders, Ruben G. G.; Sowa, Sven T.; Brinch, Shoshy Alam; Lycke, Max; Nieczypor, Piotr; Aertssen, Sjoerd; Murthy, Sudarshan; Galera-Prat, Albert; Damen, Eddy; Wegert, Anita; Nazaré, Marc; Lehtiö, Lari; Krauss, Stefan (2020-06-08)
Waaler, J., Leenders, R. G. G., Sowa, S. T., Alam Brinch, S., Lycke, M., Nieczypor, P., Aertssen, S., Murthy, S., Galera-Prat, A., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L., & Krauss, S. (2020). Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor. Journal of Medicinal Chemistry, 63(13), 6834–6846. https://doi.org/10.1021/acs.jmedchem.0c00208
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.0c00208.
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https://urn.fi/URN:NBN:fi-fe202103056667
Tiivistelmä
Abstract
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 trans-cyclobutyl linker of the lead compound 1 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 IC₃₀ inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
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