Abstract

Development of Chemical Probes for Studying Cancer

John Spencer, Professor, University of Sussex

A number of projects from our laboratory will be presented; the common theme is based on the parallel synthesis of drug-like libraries accelerated via the use of microwave, flow and palladium catalysis. We have a specific interest in boron chemistry both for Suzuki reactions, leading to elaborated bioactive scaffolds, and as enzyme inhibitors in their own right. We will show a selective single digit micromolar inhibitor of urokinase, based on an arylboronic acid “serine trap”, shown by X-ray crystallography. We have synthesised a range of hybrid kinase-HDAC inhibitors and shown their activity in a number of assays, rationalised by molecular docking studies. Another project is based on stabilising thermally unstable p53 mutants, supported by a battery of cell and biophysical assays as well as by X-ray crystallography. One chemical probe from this study is PK7088, a pyrazole, shown to specifically act on the Y220C mutant and induce apoptosis via p53 rescue.