α-Folate receptor targeted thymidylate synthase inhibitors
Section: Section of Medicine
AL Jackman, FS Mitchell, M Green, M Forster; in collaboration with V Bavetsias, F Raynaud, N Wood, M Valenti, S Eccles, P Workman; Cancer Research UK Centre for Cancer Therapeutics; BTG International
Exploitation of the overexpression of cell membrane receptors in tumours for the selective delivery of cytotoxic drugs is an attractive mechanism for increasing tumour selectivity. The a-folate receptor (a-FR) is a glycosylphosphatidylinositol-linked transmembrane protein with high affinity for folates and some antifolates, although transport is primarily via the ubiquitously expressed reduced-folate carrier (RFC). Expression of the a-FR is very low in most adult normal tissues but is high in several tumour types, providing the rationale for developing novel antifolates that are transported primarily via the a-FR rather than by the RFC. We synthesised and patented a novel series of cyclopenta[g]quinazoline analogues of folic acid that are potent thymidylate synthase (TS) inhibitors (Ki~0.2 to 1nM) and at least 500-fold more selective for human tumour cell lines with high expression of the a-FR (transfected or constitutive) compared with those with very low expression levels. A pharmacokinetic study in KB tumour bearing mice demonstrated selective retention of BGC945 in tumour compared with normal tissues. Furthermore, pharmacodynamic measurements demonstrated TS inhibition only in the tumour. We have been developing an in vivo model for evaluating the efficacy and toxicity of TS inhibitors in mice. This involves injection of pegylated thymidine phosphorylase to reduce the plasma dThd from ~1mM to those levels found in humans (~0.01mM). BGC945 is in the chemistry scale up phase in preparation for preclinical toxicology and clinical study.
External Funding: Cancer Research UK, BTG International
In the Section of Medicine
