Inhibitors of Cdc25 Phosphatases; Potential Anti-Cancer Drugs and Tools for Chemical Genetics
Author(s)
Collins, James Charles
Type
Thesis or dissertation
Abstract
Cdc25 phosphatases play a crucial role in the regulation of the cell cycle, and overexpression of the three known isoforms has been directly correlated with poor cancer prognosis. Inhibition of this enzyme could prove to be an effective therapeutic strategy, but the most potent reported inhibitors lack specificity and an appropriate mechanism of action. Furthermore, more basic research is needed into the structure and precise cellular function of the different cdc25 isoforms. Following a literature survey, panels of novel inhibitors modelled on the natural product dysidiolide and reported quinonoid compounds were synthesised. Initial phosphatase assay results with cdc25A discouraged any further synthesis of related inhibitors. The untagged catalytic domain of each isoform was prepared, expressed and purified to carry out NMR structural studies. However, preliminary spectra showed a high degree of conformational flexibility that made further analysis prohibitively difficult. Extensive screening of crystallisation conditions also did not prove successful. As an alternative strategy, a ligand-based virtual screening approach using an optimised selection of reported inhibitors resulted in discovery of diarylthiazoles as novel, potent and drug-like inhibitors of cdc25 and the related phosphatase VHR. Some of these compounds also demonstrated potent anti-proliferative activity against a panel of cell lines. Parallel synthesis of a wide range of diarylthiazole analogues using a regioselective, sequential Pd-coupling approach proved moderately successful, identifying promising novel inhibitors for further development, although without significantly increasing the binding affinity. Screening of a wide range of commercially-available compounds chosen by a substructure analysis identified further promising inhibitors, which compare favourably with the best literature compounds. Attempts to develop novel methodology for the rapid and divergent synthesis of aminothiazoles ultimately proved unsuccessful with respect to various approaches to the difficult C-N bond formation, but simple conditions were found for the synthesis and Suzuki coupling of a highly electron-rich aminothiazole C4-triflate.
Date Issued
2011
Online Publication Date
2013-06-05T09:55:56Z
Date Awarded
2011-02
Advisor
Mann, David
Armstrong, Alan
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)