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Discovery of a novel series of tankyrase inhibitors by a hybridization approach

DOI: 10.1021/acs.jmedchem.7b00883 DOI Help

Authors: Upendra Rao Anumala (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Jo Waaler (Oslo University Hospital) , Yves Nkizinkiko (University of Oulu) , Alexander Ignatev (University of Oulu) , Katina Lazarow (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Peter Lindemann (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Petter Angell Olsen (Oslo University Hospital) , Sudarshan Murthy (University of Oulu) , Ezeogo Obaji (University of Oulu) , Alexander G. Majouga (Moscow State University) , Sergey V. Leonov (National University of Science and Technology MISiS; Moscow Institute of Physics and Technology (State University)) , Jens Peter Von Kries (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP); Berlin Institute of Health (BIH)) , Lari Lehtiö (University of Oulu) , Stefan Krauss (Oslo University Hospital) , Marc Nazaré (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP); Berlin Institute of Health (BIH))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2017

Open Access Open Access

Abstract: A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with a biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity towards other Poly(ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in-vitro ADME profile as well as good oral bioavailability in mice, rats and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.

Journal Keywords: Peptides and proteins; Assays; Rodent models; Inhibitors; Nicotinamide

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I02-Macromolecular Crystallography

Other Facilities: ID23-1 at ESRF

Added On: 27/11/2017 08:52


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)