The overall long-term objective of this NCDDG is to develop novel anti- cancer drugs based on inhibition of Ras farnesylation, a lipid modification required for plasma membrane association and malignant transformation activity of Ras. The overall goal of Program #2 within the NCDDG is to evaluate and develop Ras farnesyltransferase (FTase) inhibitors into pharmacological agents selective for human tumors with aberrant Ras function.
The specific aims of Program #2 are: 1) to investigate the structural requirements of inhibition of farnesylation. The ability of the molecules synthesized by Program #1 to inhibit Ras FTase in vitro and Ras processing/plasma membrane association in intact cells will be investigated, 2) to determine the selectivity of the molecules identified in specific aim 1) towards inhibition of farnesylation. The ability of FTase inhibitors to inhibit geranylgeranyltransferase I (GGTase I) and GGTase II, two closely related enzymes, as well as the ability of inhibitors to block geranylgeranylation and farnesylation of several proteins in cultured cells will be evaluated, 3) to investigate the selectivity of FTase-specific inhibitors to inhibit DNA synthesis and proliferation and to reverse ras-dependent transformation. Cells transformed with oncogenes that use a ras-dependent pathway and a ras-independent pathway as well as cells transformed with oncogenes that encode farnesylated, geranylgeranylated or myristylated Ras will be used to evaluate this selectivity issue, 4) to determine the antitumor efficacy in a nude mouse xenograft model of FTase-specific inhibitors against human tumors that express mutated ras oncogenes, 5) to determine the selectivity of Ftase inhibitors to block in vivo tumor growth of human tumors expressing K-, N- and H-ras oncogene mutations and 6) to evaluate the antitumor efficacy of FTase inhibitors against human tumors with an upregulated Ras function due to activation of events upstream of Ras as well as human tumors that overexpress non-mutated Ras. The work described in Program #2 will enhance our understanding of the mechanism of inhibition of FTase and the selective use of this molecular target to interfere with in vivo tumor growth. Furthermore, the synergy born out of the efforts of the interrelated and interdependent Programs #1, #2 and #3 of this NCDDG will lead to the development of selective anti-cancer drugs against human tumors with aberrant Ras function.
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