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Title: Inhibitors of the tankyrases, triple-function targets in the cancer cell
Author: Paine, Helen Angharad
ISNI:       0000 0004 5358 9648
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2014
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The tankyrases are poly(ADP-ribose)polymerases that are overexpressed in many cancers. They operate through three distinct mechanisms; they regulate the elongation of telomeres, are a feature of Wnt-signalling (aberrant in many cancers) and are vital for the correct functioning of the mitotic spindle during mitosis. Thus the tankyrases are an intriguing target for a new therapy. A library of isoquinolin-1-ones with a variety of 3-substituents was synthesised using Pd-catalysed couplings, to probe the nicotinamide-binding site and adjacent hydrophobic pocket. Positions-4 and -5 were also accessed using carbanion chemistry. Preliminary ranging studies were conducted against tankyrase-2. Key Structure-Activity Relationship (SAR) features for potent inhibition included a para-substituted 3-aryl group and a small hydrophobic group in position-5. New inhibitors were designed with extensions and steric bulk in the 3-aryl region, designed to reach further into and test the capacity of the hydrophobic pocket. Removal of the 5-amine improved potency but worsened water-solubility. This was re-introduced through a basic tertiary aliphatic amine tethered to the 3-phenyl group. Molecular modelling and small-molecule crystal structures facilitated the understanding of the SAR. Steric clashes were apparent for inhibitors with bulky ortho-substituted 3-aryl groups, whereas para-substituted 3-aryl groups fitted well into the hydrophobic pocket. Although ortho-substituents on the 3-aryl group confer a dihedral twist between the isoquinolin-1-one and 3-aryl group, this is not responsible for the loss of activity. Fifteen isoquinolin-1-ones were selected for fuller biological evaluation, based on potent activity, SAR features and superior pharmaceutical properties. IC50 values were measured against tankyrases-1 and -2 and a counter-screen conducted against PARP-1. A number of analogues were highly anti-proliferative in the human colon carcinoma HT29 cells and human FEK4 fibroblasts; however, inhibition of tankyrases did not always correlate with this activity. A subset of potent tankyrase-2 inhibitors demonstrated good selectivity for HT29 over FEK4 cells; these also showed good inhibition of PARP-1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available