Induction of Cancer Cell Death via the Inhibition of Amino Acid Uptake
Glutamine has been known to be an essential fuel for cancer cell proliferation. Once taken in, it behaves as both a nitrogen and carbon source for the synthesis of nucleotides and amino acid. Recent studies have found that an important player in glutamine transport in cancer cells is the alanine-serine-cysteine transporter 2 (ASCT2). In cancers such as prostate, lung, and breast, ASCT2 expression is prominently increased. The organic synthesis of ASCT2 pharmacological inhibitors can suppress glutamine transport, reduce tumor size, and ultimately lead to cell death. Using molecular imaging probes, we are able to see where and how glutamine uptake is occurring in order to reach the target of interest in vivo. Glutamine uptake in non-cancerous cells is redundant, therefore ASCT2 inhibition would not be detrimental. In the Manning lab, we are working to synthesize both pharmacological inhibitors and complementary positron emission tomography (PET) tracers needed to provide novel therapeutics for cancers overly expressing ASCT2. The multi-step synthesis of these drugs, begins with a 4-aminobutanoic acid precursor. A convergent synthetic route has been developed for library synthesis of derivatives based on the current lead compound, V-9302. Upon synthesis of each novel derivative, biological assays in live cells are used to determine which compounds are the most effective inhibitors of glutamine uptake.