Grant: Project Grant

Dihydrofolate reductase (DHFR) is an important enzyme for folate metabolism and is a prominent anti-cancer and anti-inflammatory drug target. Commonly used DHFR therapies can effectively block folate metabolism, which impairs the production of building blocks needed for DNA synthesis. Despite their widespread use as cancer therapies, clinically used DHFR inhibitors frequently encounter resistance mechanisms that limit their efficacy. Resistance to classic DHFR inhibitors typically results from their similarity to dihydrofolate or due to overexpression of DHFR protein. To overcome DHFR inhibitor resistance, the proposed work uses an alternative DHFR inhibitor scaffold based on the anti-malaria drug Pyrimethamine (Pyr). As an anti-parasitic agent, Pyr binds to parasitic DHFR to halt replication of the parasite. We have recently shown that Pyr has promising anti-cancer activity, primarily through its ability to inhibit human DHFR. Using Pyr as a focal point, we will produce novel compounds that will not just inhibit DHFR, but will remove DHFR from cancer cells. This will be done using an approach known as Proteolysis Targeting Chimeras (PROTACs). PROTACs are bifunctional molecules, where one part will bind to DHFR and the other part will recruit proteins that tag DHFR for cellular destruction. We have recently demonstrated that Pyr-inspired PROTACs can block DHFR accumulation in cancer cells, which is a hallmark of DHFR inhibitor resistance. Specifically, this project aims to develop and optimize Pyr-inspired PROTACs. We will assess their ability to degrade DHFR in cancer cells and overcome DHFR inhibitor resistance. To accomplish these ambitious goals we have assembled a team with broad expertise in cancer biology, enzymology and drug discovery. We share the common aim to identify novel cancer therapies that can be used in the fight against cancer.