2. Academic Validation
  3. Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor

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

  • J Med Chem. 2020 Jul 9;63(13):6834-6846. doi: 10.1021/acs.jmedchem.0c00208.
Jo Waaler 1 2,  Ruben G G Leenders 3,  Sven T Sowa 4,  Shoshy Alam Brinch 1 2,  Max Lycke 1 2,  Piotr Nieczypor 3,  Sjoerd Aertssen 3,  Sudarshan Murthy 4,  Albert Galera-Prat 4,  Eddy Damen 3,  Anita Wegert 3,  Marc Nazaré 5,  Lari Lehtiö 4,  Stefan Krauss 1 2
Affiliations

Affiliations

  • 1 Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway.
  • 2 Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway.
  • 3 Mercachem BV, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • 4 Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 5400, 90014 Oulu, Finland.
  • 5 Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
PMID: 32511917 DOI: 10.1021/acs.jmedchem.0c00208
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 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.

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