2. Academic Validation
  3. Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

  • J Med Chem. 2021 Dec 23;64(24):17936-17949. doi: 10.1021/acs.jmedchem.1c01264.
Ruben G G Leenders 1,  Shoshy Alam Brinch 2 3,  Sven T Sowa 4,  Enya Amundsen-Isaksen 2 3,  Albert Galera-Prat 4,  Sudarshan Murthy 4,  Sjoerd Aertssen 1,  Johannes N Smits 1,  Piotr Nieczypor 1,  Eddy Damen 1,  Anita Wegert 1,  Marc Nazaré 5,  Lari Lehtiö 4,  Jo Waaler 2 3,  Stefan Krauss 2 3
Affiliations

Affiliations

  • 1 Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • 2 Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
  • 3 Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway.
  • 4 Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
  • 5 Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
PMID: 34878777 DOI: 10.1021/acs.jmedchem.1c01264
Abstract

Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the Wnt/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including Cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC50 inhibition in a cellular (HEK293) Wnt/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon Cancer cell line COLO 320DM.

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