Structure and Function of the Reduced Folate Carrier
Abstract
Career Goals: My explicit career goal is an academic research position studying cancer-associated proteins, in particular, the atomic structure of proteins that import or export chemotherapy drugs. With my previous Ph.D. focused on the atomic structure ion channels and transporters critical for the activity of the heart and nervous system, I am well trained in the field. Notably, all of my post-graduate publications include atomic structures, strong results in an exceptionally challenging field of study. I am now transitioning my focus and training to similar protein families, with the distinction of their clinical roles in cancer. Structures of cancer-associated transporters, such as the Reduced Folate Carrier involved in colon, pancreatic, rectal, and gastric cancers, are necessary to the design of new chemotherapy drugs. In particular to the Reduced Folate Carrier, naturally occurring mutations change the effectiveness of many chemotherapies. A structure will explain the effects of these mutations and be used in the design of new drugs or patient-specific treatment regiments that avoid these consequences. The proposed research development plan will allow me to complete the crystallization of the Reduced Folate Carrier. With this we can describe the atomic structure of the protein and address directly the questions of drug binding and transport. This will then serve as a guide to understand drug mechanism and drug design. Scientific Objective: The structure will be best applied in Drug Discovery. This work will serve as a template for developing a new generation of folate mimicking chemotherapy drugs. In addition, this structure will allow for tailored treatment of individuals with naturally occurring mutations in the protein, which alters the typical effectiveness of current drugs. Patients will benefit from new, more precise, chemotherapies. All patients on folate mimicking chemotherapy drugs will benefit from this study. New drugs will improve current chemotherapies, and allow for new drugs which target the Reduced Folate Carrier (a novel mechanism). Clinical Applications will stem from tailored chemotherapy regiments. The structure will be of direct utility to those individuals with mutant forms of the Reduced Folate Carrier, possibly guiding alternative therapies. The biggest payoff, however, is the development of new folate mimicking drugs and particularly new drug classes. Direct risks to patients are small, as all chemotherapy regiments will use drugs that have been through, or will go through, clinical trials. The structure will provide quick insights, but most especially will speed long-term drug development. The structure may be of immediate utility in the treatment of cancers for those individuals with mutant forms of the Reduced Folate Carrier, suggesting alternate drugs based upon apparent functional defects. Structure-based drug design is a significantly longer process. However, the interest in folate mimicking drugs has already produced a large library of chemicals, which can be quickly compared to the structure, speeding development. The structure will have broad impact, addressing multiple cancers. Atomic structures is a critical strategically asset in the improvement of cancer treatments, though not always of immediate benefit in the clinic. Drug design involving the Reduced Folate Carrier is currently limited to trial and error of numerous arbitrary drug formulations using laborious and slow experimental techniques. With a structure, a drug can be designed to precisely fit the protein, validated experimentally, and pushed into the drug pipeline quickly. Benefit: This work will directly benefit Service members, their families, and beneficiaries by accelerating the development of new and novel chemotherapies. Folate mimicking drugs, imported by the Reduced Folate Carrier, are among the oldest and most commonly used chemotherapeutics. Improvement in their effica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610153
Entities
People
- David Sauer
Organizations
- Grossman School of Medicine
- United States Army