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Identification of novel, potent inhibitors of PAICS within the de novo purine synthetic pathway to target the treatment of metastatic breast cancer


1Cassandra Rigby, 1Zaynab Neetoo-Isseljee, 1Craig Southern, 1Michelle Newman, 1Janet Brownlees, 1David Whalley, 1Keith Ansell, 1Peter Coombs, 1Chido Mpamhanga, 1Simon Osborne, 1Debra Taylor, 2Nils Visser and 2Daniel Peeper

1 MRC Technology Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD
2 Netherlands Cancer Institute (NKI), Department of Molecular Oncology, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

PAICS, a bi-functional enzyme in the de novo purine biosynthetic pathway, is overexpressed in a number of tumour cell types and has recently been associated with an aggressive, tumorigenic phenotype in breast, prostate and lung cancer. In vitro, PAICS knock-down inhibits cell proliferation and migration/invasion. Moreover, PAICS knock-down has been shown to reduce tumour burden in vivo. PAICS catalyses the conversion of AIR to CAIR to yield SAICAR, a metabolic intermediate shown to induce sustained proliferative signalling in cancer cells through allosteric regulation of PKM2. The potential reliance of cancer cells upon de novo purine synthesis to support their rapid growth would therefore indicate PAICS as an attractive anti-cancer target.
Following a fragment and enzyme-based screen and medicinal chemistry programme, we have used a series of cell based assays to profile PAICS inhibitors against a panel of breast cancer cell lines. Here we report the inhibition of breast cancer cell growth and migration following treatment with PAICS inhibitors. The anti-proliferative activity of PAICS inhibitors were compared to clinically relevant anti-metabolite/chemotherapeutic agents. The generation of potent and selective PAICS inhibitors will allow further exploration of the role of the de novo biosynthetic pathway in cancer cell biology, with potential for the development of novel anti-cancer therapeutics.
(PAICS: phosphoribosylaminoimidazole carboxylase/ phosphoribosylaminoimidazole succinocarboxamide synthetase)
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