Ras malignant transformation requires posttranslational modification by
farnesyltransferase (FTase). Here we report on the design and antitumor activity, in monotherapy as well as in combination
therapy with
cytotoxic agents, of a novel class of non-
thiol-containing
peptidomimetic inhibitors of FTase and the closely related family member
geranylgeranyltransferase I (
GGTase I). The non-
thiol-containing FTI-2148 is highly selective for FTase (IC50, 1.4 nM) over
GGTase I (IC50, 1700 nM), whereas
GGTI-2154 is highly selective for
GGTase I (21 nM) over FTase (IC50, 5600 nM). In whole cells, the corresponding methylester
prodrug FTI-2153 is >3000-fold more potent at inhibiting H-Ras (IC50, 10 nM) than Rap1A processing, whereas
GGTI-2166 is over 100-fold more selective at inhibiting Rap1A (IC50, 300 nM) over H-Ras processing. Furthermore, FTI-2153 was highly effective at suppressing oncogenic H-Ras constitutive activation of
mitogen-activated protein kinase and human
tumor growth in soft
agar. FTI-2148 suppressed the growth of the human
lung adenocarcinoma A-549 cells in nude mice by 33, 67, and 91% in a dose-dependent manner. Combination
therapy of FTI-2148 with either
cisplatin,
gemcitabine, or
Taxol resulted in a greater antitumor efficacy than monotherapy.
GGTI-2154 in similar antitumor efficacy experiments is less potent than FTI-2148 and inhibits
tumor growth by 9, 27, and 46%. Combination
therapy of
GGTI-2154 with
cisplatin,
gemcitabine, or
Taxol is also more effective. Finally, FTI-2148 and
GGTI-2154 are 30- and 33-fold more selective and 30- and 16-fold more potent in whole cells than our previously reported
thiol-containing
FTI-276 and
GGTI-297, respectively. Thus, our results demonstrate that this highly potent and selective novel class of non-
thiol-containing
peptidomimetics inhibits human
tumor growth in whole animals and that combination
therapy with
cytotoxic agents is more beneficial than monotherapy.