Tumor Targeting by Small Molecule Therapeutics for a Proton-Coupled Folate Transporter (PCFT)

Case ID:


PCFT plays an important role in intestinal folate absorption.  The recently cloned proton-coupled folate transporter (PCFT/SLC46A1) is the primary transporter mediating intestinal folate absorption.  PCFT displays optimal folate influx activity at acidic pH and recognizes folic acid, reduced folates (e.g. 6S-5-CH3-THF) and the antifolate methotrexate (MTX) as transport substrates with comparable high affinities (Km = 0.5–2 μM).  Moreover, PCFT exhibits an extremely high transport affinity for the antifolate anticancer drug pemetrexed (Alimta) with a transport Km of 90 nM. Belonging to the solute carrier superfamily (i.e. SLC) of transporters, PCFT is a representative of various proton-coupled low pH transport systems that mediate intestinal absorption of various essential nutrients including vitamins, amino acids, peptides, metal-ions and various organic anions. Our researchers have synthesized cytotoxic folate analogs that are selective for PCFT over RFC, the reduced folate carrier.  The analogs are similar to the clinically-used antifolate drug Alimta.


This invention involves a series of pyrrolopyrimidine antifolate analogs that show selective cytotoxicity toward solid tumor cells such as ovarian, prostate, or breast cancer cells that express significant levels of the low pH "proton-coupled folate transporter" (or PCFT). Cytotoxicity is a reflection of transport activity by PCFT and a complete lack of transport activity via the major tissue folate transporter, termed RFC.  Like RFC, PCFT is expressed broadly in normal tissues and solid tumors; RFC is expressed at high levels in leukemias whereas PCFT is not.  Even if both transporters are present, selective targeting of solid tumors expressing PCFT with small molecule inhibitors is possible due to its acidic pH optimum (pH 5.5-6.5) for transport, conditions that exist in many solid tumors but are rarely found in normal tissues outside of the proximal small intestine. RFC shows a neutral pH optimum and is inactive at acidic pH. No PCFT-selective cytotoxin has ever been described. A secondary (fortuitous)  feature  of these  analogs  is that they are potent  inhibitors  of the de novo purine biosynthetic enzyme, glycinamide formyltransferase  (GARFTase) both in cell free and cellular systems.

Technology Advantages

- Potential antitumor drugs targeting tumors expressing PCFT

- Possibly anti-ovarian, prostate and breast cancers

- Ability to also target folate receptor-expressing tumors

Patent Status

Issued - 8,252,804


Patent Information:
For Information, Contact:
Joan Dunbar
Associate Vice President for Technology Commercialization
Wayne State University
(313) 577-5542
Larry Matherly
Aleem Gangjee
Analog or Analogue
Breast Cancer
Cancer Therapies
Drug Delivery
Ovarian Cancer
Prostate Cancer