Controlled Exploration of Structural Databases: The Case of Farnesyl Transferase Inhibitors

Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC50 of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras #1, as well as selectivity (ratio of IC50 on parental RAT2 cells/ IC50 on Ras#1 cells > 2000). Moreover this compound also showed encouraging “in vivo” activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.