Folate Receptor Targeted Thymidylate Synthase Inhibitors



Antifolate drugs used for cancer treatment lack the level of tissue ­targeting desired by the new drug development paradigm. This is because their most pharmacologically relevant cell membrane transporter (the reduced-folate carrier [RFC]) and intracellular targets are not tumor specific. A number of folate receptor (FR)-targeted agents for the imaging and treatment of cancer have entered clinical studies in the last few years. Tumor targeting is achievable because FRs, most notably FRα, are present and functionally active for folate transport in many tumors but not normal tissues. Evaluation of a range of antifolate drugs pointed to a low level of selectivity for FR-expressing tumor cells even when the RFC and FR were both expressed. However, clinical evidence suggests that uptake into normal proliferating tissues by the high capacity RFC remains a major hurdle such that it is not possible to realize their potential for FR-mediated tumor targeting. Compounds were discovered that were not substrates for the RFC and were, therefore, able to selectively target FR-expressing cultured cells. Here, data are discussed on the ­prototypical FRα-targeted thymidylate synthase (TS) inhibitor, ONX 0801 ­(formerly BGC 945; CB300945) which showed a remarkable level of tumor selectivity in vivo. Pharmacodynamic endpoints for TS inhibition have been developed and are being used in an ongoing Phase 1 clinical study. Finally, potential opportunities are discussed for therapeutic intervention of FRβ-expressing leukemias and inflammatory cells by TS inhibitors.


Folate receptor ONX 0801 BGC 945 Thymidylate synthase Antifolates 


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Section of MedicineInstitute of Cancer ResearchSuttonUK

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