5NOB

Crystal structure of human tankyrase 2 in complex with OD336

Summary for 5NOB

• Entry DOI: 10.2210/pdb5nob/pdb
• Descriptor: Tankyrase-2, 1-[3-[4-(2-chlorophenyl)-5-pyrimidin-4-yl-1,2,4-triazol-3-yl]cyclobutyl]-2-oxidanylidene-3~{H}-benzimidazole-5-carbonitrile, ZINC ION, ... (4 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 2
• Total formula weight: 55668.14

Authors

Ignatev, A.,Lehtio, L. (deposition date: 2017-04-11, release date: 2017-11-29, Last modification date: 2024-01-17)

Primary citation

Anumala, U.R.,Waaler, J.,Nkizinkiko, Y.,Ignatev, A.,Lazarow, K.,Lindemann, P.,Olsen, P.A.,Murthy, S.,Obaji, E.,Majouga, A.G.,Leonov, S.,von Kries, J.P.,Lehtio, L.,Krauss, S.,Nazare, M.
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach.
J. Med. Chem., 60:10013-10025, 2017

PubMed 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 biochemical and cellular IC values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward 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.

PubMed: 29155568
DOI: 10.1021/acs.jmedchem.7b00883

Experimental method

X-RAY DIFFRACTION (1.85 Å)