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Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor

Item Type:Article
Title:Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor
Creators Name:Waaler, J. and Leenders, R. and Sowa, S.T. and Alam Brinch, S. and Lycke, M. and Nieczypor, P. and Aertssen, S. and Murthy, S. and Galera-Prat, A. and Damen, E. and Wegert, A. and Nazare, M. and Lehtiö, L. and Krauss, S.
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 IC(50) 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.
Keywords:Biological Availability, Caco-2 Cells, Cell Proliferation, Drug Design, Poly(ADP-ribose) Polymerase Inhibitors, Solubility, Tankyrases, Triazoles, Animals, Mice
Source:Journal of Medicinal Chemistry
Publisher:American Chemical Society
Page Range:6834-6846
Date:9 July 2020
Official Publication:https://doi.org/10.1021/acs.jmedchem.0c00208
PubMed:View item in PubMed

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