Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor

Article abstract of DOI:10.1021/acs.jmedchem.0c00208

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 IC50 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.

Full text of DOI:10.1021/acs.jmedchem.0c00208

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Article
Pre-clinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor
Jo Waaler, Ruben Leenders, Sven T. Sowa, Shoshy Alam Brinch, Max
Lycke, Piotr Nieczypor, Sjoerd Aertssen, Sudarshan Murthy, Albert Galera-
Prat, Eddy Damen, Anita Wegert, Marc Nazare, Lari Lehtiö, and Stefan Krauss
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.0c00208 • Publication Date (Web): 08 Jun 2020
Downloaded from pubs.acs.org on June 8, 2020
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