Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics.
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.
['Nkizinkiko|Yves|Y|', 'Suneel Kumar|B V S|BVS|', 'Jeankumar|Variam Ullas|VU|', 'Haikarainen|Teemu|T|', 'Koivunen|Jarkko|J|', 'Madhuri|Chanduri|C|', 'Yogeeswari|Perumal|P|', 'Venkannagari|Harikanth|H|', 'Obaji|Ezeogo|E|', 'Pihlajaniemi|Taina|T|', 'Sriram|Dharmarajan|D|', 'Lehtiö|Lari|L|']
D060326:Chemistry Techniques, Synthetic D015195:Drug Design D004353:Drug Evaluation, Preclinical D004791:Enzyme Inhibitors D006801:Humans D062105:Molecular Docking Simulation D018716:Molecular Mimicry D009536:Niacinamide D011799:Quinazolines D013329:Structure-Activity Relationship D038501:Tankyrases D060449:Wnt Signaling Pathway
Tankyrase Inhibition Cancer Poly(ADP-ribose)polymerase Protein crystallography Virtual screening Wnt-signalling