Folate-based drugs have been employed for decades in the treatment of cancer and inflammatory disease. These drugs, commonly termed antifolates, have met with success in clinical treatments but are severely limited due to their cytotoxic effects on normal cells. A prime example is the classic antifolate methotrexate (MTX), which is still commonly used at low doses in treatment of cancer, psoriasis and arthritic disease. Higher doses of MTX lead to obvious side effects including loss of hair as MTX preferentially kills rapidly dividing cells, normal or otherwise, without discrimination. Ideally, specific antifolates that target diseased cells without affecting normal cells could be developed. In studying folate transport, researchers have discovered that human folate receptor proteins (hFRs) are overexpressed in many tumor types and also activated macrophages at the site of inflammatory conditions (e.g. arthritis). Furthermore, the expression of hFRs on normal tissue is localized such that is not exposed to drugs administered intravenously. Taken together, antifolates that are designed to be taken up specifically by hFRs could be administered intravenously with minimal toxicity to normal tissue. Our proposal seeks to advance the development of novel hFR-specific antifolate drugs through extensive structural, thermodynamic, kinetic and cell-based characterizations of the interaction of hFRs with folate and antifolate ligands. Specifically our aims are to: 1) Determine the X-ray crystallographic structures of human membrane folate receptor types 1 and 2, targets for tissue selective delivery of experimental antifolate and folate-conjugate drugs, to aid in the design of new drugs to treat cancer and inflammatory diseases;2) Elucidate the biophysical parameters of ligand binding and release by human folate receptors to ultimately delineate the desired structural features for folate-based drugs;and 3) Analyze human folate receptor mutants to identify key determinants of FRs required for trafficking and release of folates and antifolates in situ. Given the long history of folate-based drugs in disease treatment, the obvious lack of molecular insight into hFR-ligand interaction is disappointing at best. Completion of these studies will lead to a set of molecular parameters that will guide the rational design of the next generation of antifolates, leading to profound improvements in public health relating to cancer and chronic inflammatory disease.
Our proposed research program has the potential to improve public health by substantially improving the treatment of many prevalent human cancers. During chemotherapy treatment for cancer, many adverse side effects are realized by the patient due to the toxicity of the chemotherapeutic drugs in normal cells. Our work should lead to the development of novel drugs that specifically target cancer cells and therefore improve patient therapy with the added benefit of fewer side effects. Project Narrative Our proposed research program has the potential to improve public health by substantially improving the treatment of many prevalent human cancers. During chemotherapy treatment for cancer, many adverse side effects are realized by the patient due to the toxicity of the chemotherapeutic drugs in normal cells. Our work should lead to the development of novel drugs that specifically target cancer cells and therefore improve patient therapy with the added benefit of fewer side effects.
|Golani, Lalit K; Wallace-Povirk, Adrianne; Deis, Siobhan M et al. (2016) Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor Î± and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthes J Med Chem 59:7856-76|
|Wang, Lei; Wallace, Adrianne; Raghavan, Sudhir et al. (2015) 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor Î± and the Proton-Coupled Folate Transporter in Human Tumors. J Med Chem 58:6938-59|
|Wibowo, Ardian S; Singh, Mirage; Reeder, Kristen M et al. (2013) Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proc Natl Acad Sci U S A 110:15180-8|
|Campanello, Gregory C; Ma, Zhen; Grossoehme, Nicholas E et al. (2013) Allosteric inhibition of a zinc-sensing transcriptional repressor: insights into the arsenic repressor (ArsR) family. J Mol Biol 425:1143-57|
|Fu, Yue; Tsui, Ho-Ching Tiffany; Bruce, Kevin E et al. (2013) A new structural paradigm in copper resistance in Streptococcus pneumoniae. Nat Chem Biol 9:177-83|