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Selective Inhibition of Human Tankyrases | 2014 230226 789521 9 ISBN 978-952-12-3022-6 Mohit Narwal

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Selective Inhibition of Human Tankyrases | 2014 230226 789521 9 ISBN 978-952-12-3022-6 Mohit Narwal Mohit Narwal | Selective Inhibition of Human Tankyrases | 2014 Mohit NarwalTankyrases | Selective Inhibition of Human Mohit Narwal Selective Inhibition of Human Tankyrases Pharmaceutical Sciences Department of Biosciences Åbo Akademi University Turku, Finland 9 789521 230226 2014 ISBN 978-952-12-3022-6 Mohit Narwal Mohit Narwal was born on January 20, 1984 in Nahan, H.P., India. He did his Bachelor and Master of Science in Biotechnology from Panjab University and IIT Roorkee, respectively in India. This PhD thesis work has taken place under the supervision of Dr. Lari Lehtiö at Phar- maceutical Sciences, Åbo Akademi University and Faculty of Biochemistry and Molecular Medicine, University of Oulu during 2009-2014. Åbo Akademi University Press Tavastgatan 13, FI-20500 Åbo, Finland Tel. +358 (0)2 215 3478 E-mail: [email protected] Sales and distribution: Åbo Akademi University Library Domkyrkogatan 2–4, FI-20500 Åbo, Finland Tel. +358 (0)2 -215 4190 E-mail: [email protected] Selective Inhibition of Human Tankyrases Mohit Narwal Pharmaceutical Sciences Department of Biosciences Åbo Akademi University Turku, Finland 2014 Supervisor Dr. Lari Lehtiö Docent Biocenter Oulu Faculty of Biochemistry and Molecular Medicine University of Oulu Finland Reviewer Dr. Tommi Kajander Docent, Institute of Biotechnology University of Helsinki Finland And Dr. Jens Preben Morth Center for Molecular Medicine University of Oslo Norway Opponent Dr. Herwig Schüler PI Structural Biochemistry Department of Medical Biochemistry and Biophysics Karolinska Institutet Sweden Cover: Crystal structure of tankyrase 2 in complex with IWR-1 My photo: Picture by Bhargav Prabhakar ISBN 978-952-12-3022-6 Painosalama Oy – Turku, Finland 2014 Table of Contents ORIGINAL PUBLICATIONS ............................................................................... I CONTRIBUTIONS OF THE AUTHOR ............................................................... II ACKNOWLEDGEMENTS .................................................................................. III ABSTRACT......................................................................................................... VI ABBREVIATIONS ........................................................................................... VIII 1 REVIEW OF THE LITERATURE ................................................................... 1 1.1 Introduction ................................................................................................ 1 1.1.1 ARTD activation, poly(ADP-ribosyl)ation reaction and ARTD catabolism ............................................................................. 2 1.2 ARTDs and their functions ......................................................................... 3 1.2.1 ARTD1 ............................................................................................. 3 1.2.2 ARTD2 ............................................................................................. 4 1.2.3 ARTD3 ............................................................................................. 5 1.2.4 ARTD4 ............................................................................................. 5 1.2.5 Mono (ADP-ribosyl) transferases .................................................... 6 1.3 Tankyrases .................................................................................................. 6 1.3.1 Crystal Structure ............................................................................... 7 1.3.2 Tankyrase modifications .................................................................. 8 1.3.3 The SAM domain ............................................................................. 9 1.3.4 The ankyrin repeats and the target specificity .................................. 9 1.4 Functions of tankyrases ............................................................................ 10 1.4.1 Telomere maintenance ................................................................... 11 1.4.2 Role in Wnt signaling pathway ...................................................... 13 1.4.3 GLUT4 vesicle translocation ......................................................... 14 1.4.4 Mitosis ............................................................................................ 15 1.4.5 Proteasome regulation .................................................................... 16 1.5 Role of tankyrases in cancer ..................................................................... 17 1.5.1 Role of tankyrases in viral infections ............................................. 18 1.5.2 Role of tankyrases in obesity and other diseases ........................... 18 1.6 Drug development and available ARTD inhibitors .................................. 19 1.6.1 Properties of a drug candidate and screening strategy ................... 19 1.6.2 Pharmacodynamics and pharmacokinetics ..................................... 20 1.6.3 Clinical phases ............................................................................... 20 1.6.4 PARP inhibitors and selective tankyrase inhibitors ....................... 21 1.6.5 Tankyrase inhibitors binding to the nicotinamide site ................... 21 1.6.6 Adenosine site and dual-site binding inhibitors ............................. 22 2 AIMS OF THE STUDY .................................................................................. 24 3 MATERIALS AND METHODS .................................................................... 25 3.1 Expression vectors (I-V) ........................................................................... 25 3.2 Protein expression and purification (I-V) ................................................. 25 3.3 Activity assay (I-V) .................................................................................. 26 3.4 Optimization of assay conditions and assay repeatability (I, III) ............. 26 3.5 Screening and potency measurements (I, III, IV, V) ................................ 27 3.6 Western blot method (I, II) ....................................................................... 27 3.7 Crystallization and crystallography (II-V) ............................................... 28 4 RESULTS ........................................................................................................ 29 4.1 Adaptation of an assay for screening the compounds .............................. 29 4.1.1 Protein expression and purification (I-V) ....................................... 29 4.1.2 Assay optimization (I, III) .............................................................. 29 4.1.3 Assay validation (I, III) .................................................................. 30 4.1.4 Validatory Screening and potency measurements (I) ..................... 30 4.2 Identifications of flavones as potent and selective tankyrase inhibitors (III, IV) ..................................................................................... 31 4.2.1 Screening of the flavonoids library and binding mode of flavones (III) ................................................................................... 31 4.2.2 Screening of the flavones with single substitutions and co- crystal structures (IV) ..................................................................... 32 4.2.3 Inhibition of Wnt signaling and profiling of the inhibitors (IV) ................................................................................................. 37 4.3 Inhibitor binding to adenosine site (II) ..................................................... 38 4.3.1 Co-crystal structure of TNKS2 catalytic domain in complex with IWR-1 ..................................................................................... 38 4.3.2 Structure-activity relationship studies of IWR-1 analogues ........... 38 4.3.3 IWR-1 selectivity ........................................................................... 39 4.4 Characterization of known ARTD inhibitors (V) ..................................... 40 4.4.1 Screening of the inhibitors and potency measurements ................. 40 4.4.2 Binding modes of the compounds .................................................. 41 4.4.2.1 Binding modes of Phenanthridinone (16) and TIQ- A (18) .............................................................................. 42 4.4.2.2 Binding mode of PJ-34 (17) ............................................ 42 4.4.2.3 Binding mode of Rucaparib (29) .................................... 42 4.5 Substrate Binding (II, V) .......................................................................... 43 4.5.1 Co-crystal structure of TNKS2 catalytic domain in complex with nicotinamide (II)..................................................................... 43 4.5.2 Co-crystal structure of TNKS2 catalytic domain in complex with EB-47 (V) ............................................................................... 43 5 DISCUSSION .................................................................................................. 46 5.1 The screening assay (I, III, IV) ................................................................. 46 5.2 Flavones as tankyrase inhibitors (III, IV) ................................................. 47 5.3 Novel binding mode of IWR-1 (II)........................................................... 50 5.4 Inhibition of tankyrases by ARTD inhibitors (V)..................................... 50 5.5 Substrate binding (II, V) ........................................................................... 51 6 CONCLUSIONS AND FUTURE PERSPECTIVES .....................................
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