Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics

DOI: 10.1016/j.bmc.2015.06.063
PMID: 26183543

Authors: Yves Nkizinkiko (University of Oulu) , B.v.s. Suneel Kumar (Birla Institute of Technology and Science-Pilani) , Variam Ullas Jeankumar (Birla Institute of Technology and Science-Pilani) , Teemu Haikarainen (University of Oulu) , Jarkko Koivunen (University of Oulu) , Chanduri Madhuri (Birla Institute of Technology and Science-Pilani) , Perumal Yogeeswari (Birla Institute of Technology and Science-Pilani) , Harikanth Venkannagari (University of Oulu) , Ezeogo Obaji (University of Oulu) , Taina Pihlajaniemi (University of Oulu) , Dharmarajan Sriram (Birla Institute of Technology and Science-Pilani) , Lari Lehtiö (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry , VOL 23 (15) , PAGES 4139 - 4149

State: Published (Approved)
Published: August 2015

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.

Journal Keywords: Tankyrase; Poly(ADP-ribose)polymerase; Inhibition; Cancer; Protein crystallography; Virtual screening

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 18/11/2015 14:11

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)