Method of treating cancer

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of inhibiting prenyl-protein transferases which comprises administering to a mammal in need thereof a pharmaceutically effective amount of a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl-protein transferase type I (GGTase-I).
Such an inhibitor is characterized by: a) an IC.
sub.
50 (a measurement of in vitro inhibitory activity) of less than about 5 .
mu.
M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX.
sup.
G motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
The inhibitor used in the instant method may be further characterized by one or both: b) an IC.
sub.
50 (a measurement of in vitro inhibitory activity) of less than about 1 .
mu.
M against transfer of a farnesyl residue to a protein or peptide substrate comprising a CAAX.
sup.
F motif by farnesyl-protein transferase; and c) an IC.
sub.
50 (a measurement of in vitro inhibitory activity) of less than about 100 nM against the anchorage independent growth of H-ras-transformed mammalian fibroblasts.
The inhibitor compounds useful in the instant method are also useful in the treatment of cancer and other proliferative disorders in mammals in need thereof.
In an embodiment of the invention the inhibitor compounds have inhibitory concentrations (IC.
sub.
50) of less than about 1 .
mu.
M against GGTase-I in the presence of a modulating anion.
Preferably such compounds have inhibitory concentrations (IC.
sub.
50) of less than about 500 nM against GGTase-I in the presence of a modulating anion.
Most preferably, such compounds have an IC.
sub.
50 of less than 250 nM against GGTase-I in the presence of a modulating anion.
A preferred cancer is one which is characterized by mutated K4B-Ras.
In another embodiment, the compound useful in the methods of the instant inventions is characterized by an IC.
sub.
50 (a measurement of in vitro inhibitory activity) of less than about 500 nM, but greater than about 5 nM against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX