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Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 [C. S., V. J. C., L. S. G., S. B. G., W. C. M., L. L. H., K. A. S., L. G. M., D. J. S., V. F. P., S. L. A., J. R. B., R. M. S.]; Department of Pediatrics, Yale University, New Haven, Connecticut 06510 [E. A. R., B. A. M., G. P. B.]; and Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699 [W. K., M. R.]
N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid (LY231514) is a novel pyrrolo[2,3-d]pyrimidine-based antifolate currently undergoing extensive Phase II clinical trials. Previous studies have established that LY231514 and its synthetic
-polyglutamates (glu3 and glu5) exert potent inhibition against thymidylate synthase (TS). We now report that LY231514 and its polyglutamates also markedly inhibit other key folate-requiring enzymes, including dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). For example, the Ki values of the pentaglutamate of LY231514 are 1.3, 7.2, and 65 nM for inhibition against TS, DHFR, and GARFT, respectively. In contrast, although a similar high level of inhibitory potency was observed for the parent monoglutamate against DHFR (7.0 nM), the inhibition constants (Ki) for the parent monoglutamate are significantly weaker for TS (109 nM) and GARFT (9,300 nM). The effects of LY231514 and its polyglutamates on aminoimidazole carboxamide ribonucleotide formyltransferase, 5,10-methylenetetrahydrofolate dehydrogenase, and 10-formyltetrahydrofolate synthetase were also evaluated. The end product reversal studies conducted in human cell lines further support the concept that multiple enzyme-inhibitory mechanisms are involved in cytotoxicity. The reversal pattern of LY231514 suggests that although TS may be a major site of action for LY231514 at concentrations near the IC50, higher concentrations can lead to inhibition of DHFR and/or other enzymes along the purine de novo pathway. Studies with mutant cell lines demonstrated that LY231514 requires polyglutamation and transport via the reduced folate carrier for cytotoxic potency. Therefore, our data suggest that LY231514 is a novel classical antifolate, the antitumor activity of which may result from simultaneous and multiple inhibition of several key folate-requiring enzymes via its polyglutamated metabolites.
1 To whom requests for reprints should be addressed, at Cancer Research Division, Lilly Research Laboratories, Drop 0540, Eli Lilly and Company, 307 E. McCarty St., Indianapolis, IN 46285. Phone: (317) 276-3520; Fax: (317) 277-3652.
Received 8/21/96. Accepted 1/17/97.
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