CB 3717

CB 3717 is a potent inhibitor of human thymidylate synthetase, competitively binding with 5,10-methylenetetrahydrofolate (Ki = 4.9 X 10(-9) M). It also competitively inhibits human dihydrofolate reductase with dihydrofolate (Ki = 2.3 X 10(-8) M). In WI-L2 human lymphoblastoid cells, CB 3717 treatment led to a significant decrease in cellular dTTP levels and a notable increase in dUMP levels, indicating a disruption in nucleotide metabolism. The growth-inhibitory effect of CB 3717 was reversed by thymidine supplementation, demonstrating that thymidylate synthetase became rate-limiting in the presence of this compound. Delayed thymidine supplementation beyond 8 hours resulted in severe cytotoxicity, underscoring the critical timing of nucleotide rescue strategies in CB 3717-treated cells[1].

[1]Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells