Cancer is the second leading cause of death in the United States with approximately 9.5 million deaths recorded in 2018. Although a wide variety of chemotherapeutic and immunotherapeutic treatments exist for various cancers, additional therapies focused on novel targets are needed to address resistant and refractory cancers. Our laboratory is interested in de novo purine biosynthesis since this pathway has been shown to be critical for rapidly replicating cancer cells. A key protein in this pathway is the bifunctional enzyme phosphoribosylaminoimidazole carboxylase succinocarboxamide synthetase (PAICS) which has been shown to be overexpressed in pancreatic, lung, prostate, bladder, and breast cancers. PAICS knockdown studies have shown decreased cell proliferation and cancer cell invasion, making PAICS an attractive anticancer target. One enzyme that encompasses PAICS, phosphoribosylaminoimidazole carboxylase also called 5-aminoimidazole ribonucleotide (AIR) carboxylase, is strongly inhibited by the product analog 4-nitro-5-aminoimidazole ribonucleotide (NAIR). NAIR is a tight binding (Ki = 0.34 nM) inhibitor of the vertebrate enzyme but does not show anticancer activity. We have hypothesized that the presence of the phosphate group precludes transport into the cell and the nucleoside is 1,000-fold less potent than the nucleotide. To address this problem, we are investigating phosphate bioisostere analogs of NAIR as well as NAIR analogs containing warheads that react covalently with a conserved Lys304 residue. Through the combination of covalent fragments and phosphate bioisosteres, we predict that NAIR-inspired analogs will have enhanced anticancer activity. The results of our studies will be presented in this poster.

Development of non-nucleotide analogs of NAIR as inhibitors of AIR carboxylase

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.