Characterizing the effects of the novel compound IRS-17 against DHFR in Human Colon Cancer

Abstract

The topic of this senior thesis is on the inhibition of an enzyme called dihydrofolate reductase (DHFR) which catalyzes the transformation of folate to tetrahydrofolate. This reaction is one of the many reactions of one-carbon metabolism that take place in the cell. At the heart of one carbon metabolism are folate molecules which function as carbon carriers – receiving and supplying one-carbon molecules with different oxidation states to many biological reactions. Folate metabolism is particularly important for the synthesis of purines, thymidine, and amino acids, all of which are essential for cell division and proliferation. This has made inhibiting folate metabolism an ideal target in combating dysregulated cellular division and proliferation in diseased conditions such as cancer. Consequently, DHFR inhibition, which disrupts folate metabolism, has been shown to reduce tumor growth in many cancer models in vitro and in vivo. This project is meant to build upon a finding that a particular small-molecule inhibitor called IRS-17 had inhibitory activity on tumor growth in-vivo. Experiments are conducted to track the activity of IRS-17 in vitro and to identify if it prevents cellular proliferation in human colon cancer cell line HCT-116 comparable to established anticancer drugs such as Methotrexate and Pemetrexed. Both drugs have anti-DHFR activity and since IRS-17 has a similar structure, it is hypothesized that it also binds DHFR. This is confirmed by isotopic labeling and metabolite tracing. Overall, the project builds a profile on IRS-17 and lays the groundwork for further experiments on its pharmacological properties.