Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA).
Extensive biochemical and pharmacological evidence indicates that LY231514 is a novel antifolate antimetabolite. LY231514 is transported into cells mainly through the reduced folate carrier system and extensively metabolized to polyglutamated forms. The polyglutamates of LY231514 inhibit at least three key folate enzymes: TS, DHFR, and GARFT, and to a lesser extent AICARFT and C1-tetrahydrofolate synthase. The combined effects of the inhibition exerted by LY231514 at each target give rise to an unusual end-product reversal pattern at the cellular level that is distinct from those of other inhibitors such as methotrexate and the quinazoline antifolates. The metabolic effects exerted by LY231514 on the folate and nucleotide pools are also quite distinct from those of MTX and LY309887. The efficient polyglutamation, longer cellular retention and the multiple folate enzyme inhibition mechanism may all have contributed directly to the exciting antitumor responses now observed in Phase I and II studies. The multitargeted inhibition mechanism of LY231514 is particularly intriguing. This new level of mechanistic insight, which has evolved from the study of LY231514, challenges the traditional concept and paradigm of antifolate drug discovery and development which focused on developing very potent and selective inhibitors of single folate enzyme targets, such as DHFR, TS or one of the enzymes along the de novo purine biosynthetic pathway. Given the complex nature of folate metabolism and the critical role of folates in maintaining the physiological functions of living systems, it is completely reasonable to suspect that agents which can interfere at multiple sites in the folate pathway may trigger and cause more biochemical imbalance in the cellular DNA and RNA synthesis of malignant cells than agents that act on a single point (Fig. 5). In conclusion, LY231514 (MTA) is a new generation antifolate antimetabolite demonstrating inhibitory activity against multiple folate enzymes including TS, DHFR and GARFT. In current phase II studies, MTA is broadly active as a single agent and is showing very encouraging antitumor activity in multiple solid tumors including colorectal, breast and non-small cell lung cancers (38-43). The every three week dosing schedule has proven to be convenient and easy to administer and the clinical toxicities of LY231514 seem to be well tolerated. More advanced and extensive clinical trials of LY231514 are currently in progress.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
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Shih
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Habeck
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Mendelsohn
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Chen
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Schultz
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D000068437:Pemetrexed; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D013552:Swine; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D011624:Pteroylpolyglutamic Acids; D013763:Tetrahydrofolates; D000068437:Pemetrexed; D006147:Guanine; C045894:lometrexol; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate