Objective

Recent studies suggest that a previously un-targeted enzyme in the de novo purine pathway; PAICS, may act as a key signalling molecule to regulate cancer cell growth and function. We evaluated PAICS gene expression in primary biopsies obtained from breast, lung, colon, melanoma and prostate cancers, and demonstrated a significant upregulation of PAICS compared to normal tissues. To genetically validate PAICS inhibition as an approach to reduce cancer growth we compared PAICS knock-out breast cancer cells (CRISPR) to wild type cells, which showed a reduced rate of proliferation in the KO. To further validate PAICS as a cancer target we developed a series of inhibitors of PAICS with good physicochemical properties and nM potency in biochemical and biophysical assays. They exhibited sub-µM potency on proliferation of a panel of breast cancer cell lines, although it was evident that some cell lines responded better than others. This differential sensitivity was further explored by testing the inhibitors against 278 cancer cell lines representing 12 different cancer types (CLIMB panel). Despite variation in response, PAICS inhibitors showed activity against all cancer types and overall blood cancers and head and neck cancers appeared to be the most sensitive. Correlation of gene expression data from the Broad Institute CCLE dataset indicated that PAICS expression did not correlate with sensitivity. Analysis of additional genes is currently ongoing and will be presented.