Mentor: Professor W. Malachowski
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan degradation enzyme that is expressed by many tumors to help escape immune detection. Normally, IDO catalyzes an initial step in the degradation of tryptophan to N-formylkynurenine leading to the formation of NAD+. Additionally, IDO is a negative regulator of T-cell activity. T-cells are sensitive to tryptophan catabolism, and depletion of tryptophan or buildup of toxic catabolites can cause T-cells to stop in the G1 phase of cell growth, and therefore cease dividing though mitosis, or can cause cell death. The initial discovery of a relationship between IDO and the immune system occurred in studies of placental trophoblasts which demonstrated IDO activation to prevent maternal immune response to paternal fetal antigens.
Cancer cells, which would normally be destroyed by the immune system, can harness IDO to prevent their destruction and cause proliferation and tumor formation. In fact, elevated levels of IDO-generated catabolites have been found to be associated with a number of cancers. Therefore, inhibition of IDO can promote antitumor immune responses, which allow a specific drug-based approach to treating cancer.
My summer research project involves the synthesis of a molecule which is expected to have inhibitory effects on the indoleamine enzyme. The synthesized molecule mimics an intermediate in the proposed mechanism of the degradation of tryptophan (figure 1), which is why the particular structure has been proposed. The synthetic pathway leading to the formation of the product can also be seen below in figure 2.