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Development and structural analysis of adenosine site binding tankyrase inhibitors

DOI: 10.1016/j.bmcl.2015.12.018 DOI Help
PMID: 26706174 PMID Help

Authors: Teemu Haikarainen (University of Oulu) , Jo Waaler (Oslo University Hospital) , Alexander Ignatev (University of Oulu) , Yves Nkizinkiko (University of Oulu) , Harikanth Venkannagari (University of Oulu) , Ezeogo Obaji (University of Oulu) , Stefan Krauss (Oslo University Hospital) , Lari Lehtio (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 26 (2) , PAGES 328 - 333

State: Published (Approved)
Published: January 2016

Open Access Open Access

Abstract: Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.

Journal Keywords: ARTD; PARP; Small-molecule; Tankyrase; Tankyrase inhibitor; WNT inhibitor; WNT signaling

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

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID14-1 at ESRF

Added On: 18/01/2016 11:14


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)