Nolatrexed (AG-337)

Description:

IC50: 1.0, 0.81 and 1.0 μM for L1210, CCRF-CEM and GC3/M TK- cell lines, respectively

Thymidylate synthase (TS) is a crucial enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for DNA biosynthesis. Thus, this enzyme is a critical target in cancer chemotherapy. Nolatrexed (AG-337) is a non-classical thymidylate synthase inhibitor.

In vitro: Nolatrexed was designed using X-ray crystallographic data from the TS molecular modeling and folate binding site. It is a non-classical TS inhibitor in that it lacks a terminal glutamate side chain and is uncharged at physiological pH. Nolatrexed does not require a specific transport mechanism to enter into cells and, once within the cell, is not a substrate for the enzyme folyl polyglutamate synthetase [1].

In vivo: When nolatrexed was administered to nude mice bearing Bu25TK- tumor xenografts, a time-dependent increase in antitumor activity was observed [1].

Clinical trial: Phase I clinical studies showed that Nolatrexed can be safely administered to cancer patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects [2].

Reference:
[1] Hughes AN, Rafi I, Griffin MJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV.  Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res. 1999 Jan;5(1):111-8.
[2] Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH.  Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131-41.