STRUCTURE, CHEMISTRY, AND BIOLOGY OF ACTINOPLANIC ACIDS - POTENT INHIBITORS OF RAS FARNESYL-PROTEIN TRANSFERASE

The ras oncogene is found mutated in 50% of colon and 90% of pancreatic carcinomas. Farnesyl-protein transferase (FPTase) catalyzes farnesylation of the Ras protein, which is the essential step for the association of Ras with the plasma membrane, a critical requirement for Ras-mediated cell-transforming activity. Continued search for FPTase inhibitors led to the discovery of actinoplanic acid A and B, novel and potent inhibitors of the enzyme. We report here the details of the isolation, structure elucidation, chemistry, and biological activity of actinoplanic acid A and a significantly more active congener, actinoplanic acid B. Both of these compounds are highly functionalized 30-carbon chain length polyketides terminating with a carboxylic acid group. They are esterified with two units of carballylic acid. Actinoplanic acid A is cyclized into a macrocyclic bis-lactone, while the more potent acid B is acyclic. Both acids A and B inhibit farnesyl-protein transferase (FPTase) with IC50's of 230 and 50 nM and K-i values of 98 and 8 nM, respectively. The inhibition of FPTase by acids A and B is competitive with respect to farnesyl pyrophosphate (FPP) and uncompetitive with respect to Ras-CVIM, the peptide substrate.