Ag2034

OSI-7904L (25, OSI) is being developed as a liposomal formation of GW1843 with phase II trials under way against a variety of tumor types including colorectal, gastric, gallbladder and biliary. Combination studies have also initiated with cisplatin and oxoplatin.

OSI behaves as a classical antifolate, but is an unusual tricyclic inhibitor of TS. X-ray analysis of OSI bound to Escherichia coli TS showed the tricyclic unit bound in a fashion similar to other inhibitors and the folate cofactor, but the enzyme distorts to accommodate the side chain resulting in dislocations of active-site amino acids. The folate-binding site is nearly identical in E. coli and human TS.

OSI evolved from an original series of simple benzoquinazolines (32). While the original compounds were highly potent TS inhibitors (20 nM), they had poor cellular activity. Using the benzoquinazoline as a pterin substitute, the group prepared para-aminobenzoylglutamate analogs attached to the 9-position. Cyclization of the para-aminobenzoylglutamate of typical folate inhibitors to the lactam of OSI had little effect on TS inhibition, but it resulted in improved transportability and a nearly 200-fold increase in FPGS activity. Enzyme kinetic analysis has shown OSI inhibition of TS is noncompetitive with respect to both TS substrates. OSI is actively transported into cells by the RFC, and is a substrate for FPGS. Its polyglutamation properties are unique, however, in that the diglutamate is the primary product. It has been shown that polyglutamation is not required for potent TS inhibition.95

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