5AKW

Crystal structure of TNKS2 in complex with 2-(4-chlorophenyl)-1,2,3,4- tetrahydroquinazolin-4-one

Summary for 5AKW

• Entry DOI: 10.2210/pdb5akw/pdb
• Related: 5AKU
• Descriptor: TANKYRASE-2, ZINC ION, (2S)-2-(4-chlorophenyl)-2,3-dihydro-1H-quinazolin-4-one, ... (6 entities in total)
• Functional Keywords: transferase, protein-ligand complex, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 2
• Total formula weight: 55724.10

Authors

Nkizinkiko, Y.,Lehtio, L. (deposition date: 2015-03-05, release date: 2015-07-29, Last modification date: 2024-01-10)

Primary citation

Nkizinkiko, Y.,Suneel Kumar, B.V.S.,Jeankumar, V.U.,Haikarainen, T.,Koivunen, J.,Madhuri, C.,Yogeeswari, P.,Venkannagari, H.,Obaji, E.,Pihlajaniemi, T.,Sriram, D.,Lehtio, L.
Discovery of Potent and Selective Nonplanar Tankyrase Inhibiting Nicotinamide Mimics.
Bioorg.Med.Chem., 23:4139-, 2015

PubMed Abstract: Diphtheria toxin-like ADP-ribosyltransferases catalyse a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signalling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, we identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compounds showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures we designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compound almost 100-fold (from 11 μM to 150 nM). The most potent compounds were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.

PubMed: 26183543
DOI: 10.1016/J.BMC.2015.06.063

Experimental method

X-RAY DIFFRACTION (2.07 Å)