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Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor.

A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.

Novel tricyclic FPT inhibitors with submicromolar FPT activity are described. Greatly enhanced FPT activity is realized with phthaloyl derivatized amino compound 2k, which showed FPT inhibitory activity of IC50 = 0.66 μM. Sulfonamides 5g and 50 were also found to be potent FPT inhibitor. SAR resulting from a variety of tricyclic amino acids and sulfonamide derivatives is discussed.

A previously described cembranolide diterpene from Lobophytum cristagalli was identified as a potent (IC50 0.15 μM) inhibitor of farnesyl protein transferase (FPT). The compound showed selectivity for FPT as compared to the closely related enzyme geranylgeranyl protein transferase-1 (IC50 5.3 μM). Kinetic evaluation suggests that this compound competes with the protein/peptide farnesyl acceptor substrate, and not with farnesyl pyrophosphate for inhibition of FPT.

The condensation of indolo[2,3-a]-carbazole (12) with 2,5-dimethoxytetrahydrofuran derivatives gave cyclofuranosylated compounds (e.g. 13), which were converted via dibromocompounds to the dinitriles (e.g. 25). Hydrolysis, hydrolysis-reduction and thiolysis afforded imides, lactams (e.g. 27) and their thio analogs. These compounds were potent inhibitors of the protein kinase C family.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.