25 OSI-7904L (OSI)

Nolatrexed (24, NTX) is a TS inhibitor targeted to the folate-binding site of the TS enzyme. Like TMTX, NTX is a nonclassical type A antifolate that does not contain a glutamate substrate for FPGS and does not require active transport into cells through the RFC, thus potentially overcoming resistance associated with both mechanisms. NTX is currently in phase III clinical trials for the treatment of hepatocellular carcinoma. NTX is also in phase II studies in combination with docetaxel for the treatment of breast, lung, head, and neck cancers. NTX was designed with the aid of x-ray crystallographic data using E. coli TS. The 6-methyl group of NTX is a key substituent, aligning the thiopyridine in an optimal configuration, giving a 10-fold increase in human TS activity over the des-methyl analog 33.96 Conversion of the 2-methyl group to an amine resulted in a further six-fold increase in potency resulting in the 15 nM TS inhibitor NTX.97 Cell lines resistant to NTX have shown increased TS activity as well as structural changes in the enzyme.98 Also P-glycoprotein-associated multidrug resistance (P-gp-MDR) has been noted.99 Dose-limiting toxicities of NTX included myelosuppression and mucositis.

Plevitrexed (26, PTX) is a potent TS inhibitor containing a tetrazole as a glutamic acid mimic. As such, PTX is a substrate for the RFC, but is not polyglutamated by FPGS, and would be considered a nonclassical type B antifolate. PTX is a noncompetitive inhibitor of TS, with respect to N5,N10-CH2-THF. PTX has been shown to be effective in cell lines with low FPGS activity. PTX was designed to be a nonpolyglutamatable analog of ICI198583 (34). Incorporation of the 2'F substituent provides increased binding, presumably by reinforcement of the preferred near-planar conformation of the benzamide through a hydrogen bond between the 2'Fand the glutamate NH. The tetrazole proved to be a highly effective gamma-acid mimic, providing a highly potent, 0.001 nM TS inhibitor.100

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