Methylbenzoprim | Dual thymidylate synthase/dihydrofolate reductase inhibitor

Methylbenzoprim (118344-71-1; Compound 19-S), a derivative of the antimalarial drug Pyrimethamine, is a non-classical potent inhibitor of mammalian dihydrofolate reductase (IC₅₀ = 3.2 nM rat liver).¹ It inhibited melanoma tumor growth both in vitro and in vivo.² Methylbenzoprim has been recently found to also inhibit thymidylate synthase (TYMS) with activity comparable to the 5-FU metabolite FdUrd.³  It was more potent than 5-fluorouracil in a panel of 4 pancreatic ductal adenocarcinoma cells lines and without TYMS overexpression that frequently leads to drug resistance.³  Methylbenzoprim inhibited tumor growth and progression in two pancreatic cancer xenograft models. Orally bioavailable.

References/Citations:

1. Griffin et al. (1989), Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series pf 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against methotrexate-resistant tumor cell line; J. Med. Chem., 32 2468
2. Tommasino et al. (2016), New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study; J. Exp. Clin. Cancer Res., 35 137
3. Guijarro et al. (2023), First-in-class multifunctional TYMS non-classical antifolate inhibitor with potent in vivo activity that prolongs survival; JCI Insight, 8 e158798