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
  • 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.

Products