Farnesyl protein transferase inhibitors targeting the catalytic zinc for enhanced binding.

Successful efforts to make farnesyl transferase (FT) inhibitors with appropriately tethered ligands designed to interact with a catalytic zinc that exist in the enzyme have been realized. Thus, by introducing either a pyridylmethylamino or propylaminolimidazole amide moieties off the 2-position of the piperidine ring, FT inhibitors with activities in the picomolar range have been achieved as exemplified by compounds 12a and 12b. An X-ray structure of 11b bound to FT shows the enhanced activity is a result of interacting with the active-site zinc.