NOVEL CLASS OF MONOGLUTAMATED ANTIFOLATES EXHIBITS TIGHT-BINDING INHIBITION OF HUMAN GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE AND POTENT ACTIVITY AGAINST SOLID TUMORS

Tight-binding inhibition of recombinant human monofunctional glycinami de ribonucleotide formyltransferase by Lometrexol (6R-5,10-dideazatetr ahydrofolate) requires polyglutamation. LY254155 and LY222306 differ f rom 5,10-dideazatetrahydrofolate in the replacement of the 1',4'phenyl ene moiety by a 2',5'-thiophene and a 2',5'-furan, respectively. Compa red to Lometrexol, the thiophene and furan analogues had 25- and 75-fo ld greater inhibitory potencies against human monofunctional glycinami de ribonucleotide formyltransferase (K-i = 2.1 and 0.77 nm, respective ly). The binding affinities of the thiophene and furan analogues for m embrane folate-binding protein from human KB cells were 6- and 350-fol d weaker than Lometrexol, respectively. Both the thiophene analogue an d 5,10-dideazatethydrofolate inhibited the in vivo growth of murine 6C 3HED lymphosarcoma, murine C3H mammary carcinoma, and human xenograft HXGC3, HC1, and VRC5 colon carcinomas by 95-100%. The thiophene analog ue was efficacious against human xenograft PANC-1, a pancreatic carcin oma which was completely resistant to 5,10-dideazatet-rahydrofolate. T hese novel antifolates represent the first monoglutamated tight-bindin g inhibitors of glycinamide ribonucleotide formyltransferase. By elimi nating the need for polyglutamation, this class of antifolates may hav e clinical activity in the treatment of solid tumors expressing low le vels of folylpolyglutamate synthetase or tumors resistant to antifolat e therapy due to increased gamma-glutamyl hydrolase activity.