) The overall long term objective of this NCDDG is to develop novel anti-cancer drugs based on inhibition of geranylgeranyltransferase I (PGGTase I). Substrates of PGGTase I such as RhoA, Rac1, Cdc42, R-Ras and TC-21 promote tumorigenesis and/or metastasis. Some of these proteins also mediate the cancer-causing activity of the ras oncogene which is implicated in 30% of human cancers. The hypothesis to be tested is that inhibition of PGGTase I will result in inhibition of tumor growth. The overall goal of Program #2 within the NCDDG is to evaluate and develop PGGTase I inhibitors into novel anticancer drugs.
The specific aims of program #2 are: 1) to investigate the structural requirements of inhibition of geranylgeranylation. The ability of the molecules synthesized by Program #1 to inhibit PGGTase I and the processing of geranylgeranylated proteins (i.e. RhoA, Rac1, Cdc42, R-Ras and TC-21) in intact cells will be investigated, 2) to determine the selectivity of the molecules identified in specific aim 1 towards inhibition of geranylgeranylation. The ability of PGGTase I inhibitors to inhibit FTase and PGGTase II, a related enzyme to PGGTase I, as well as the ability of the inhibitors to block geranylgeranylation and farnesylation of several proteins in cultured cells will be evaluated, 3) to investigate the selectivity of PGGTase I-specific inhibitors to inhibit DNA synthesis and proliferation, to alter cell cycle distribution, to promote apoptosis and to inhibit the growth in nude mice of NIH 3T3 and MCF-10A cells transformed by RhoA, Rac1, Cdc42, R-Ras and TC-21. Because Ras transformation depends on Rho proteins we will also determine the effects of PGGTase I inhibitors on NIH 3T3 cells transformed by H-, N- and K-Ras. NIH 3T3 cells transformed by EGFR, ErbB2, Src and Raf will also be used to address PGGTase I inhibitor selectivity. Finally, NIH 3T3 cells transformed with oncogenes that encode farnesylated or geranylgeranylated Rho and Ras proteins will also be used to evaluate this selectivity issue and 4) to determine the selectivity of PGGTase I inhibitors to block in vivo tumor growth in nude mice of human tumors expressing K-, N- and H-ras oncogene mutations, wild type ras as well as tumors with an upregulated wild type Ras function due to Ras overexpression or activation of events upstream of Ras. The ability of farnesylated mutants of RhoA, Rac1, Cdc42, R-Ras and TC-21 to induce resistance of human tumors to PGGTase I inhibitors will also be investigated. The work described in Program #2 will enhance our understanding of the mechanism of inhibition of PGGTase I 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 anti-cancer drugs that will broaden the spectrum of human tumors that can be treated.
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