) The overall goal of this NCDDG application is to design, synthesize and evaluate novel anticancer drugs based on inhibition of the enzyme, protein geranylgeranyltransferase I (PGGTase I). PGGTase I is an important anti-cancer drug target because substrates for PGGTase I such as RhoA, Rac1, Cdc42, R-Ras and TC-21 promote tumorigenesis and/or metastasis. Furthermore, RhoA, Rac1 and Cdc42 are also required for the transformation of Ras, an oncoprotein involved in 30% of human cancers. Finally, when human cancer cells are treated with farnesyltransferase (FTase) inhibitors, K-Ras and N-Ras become geranylgeranylated by PGGTase I. The hypothesis to be tested is that inhibition of PGGTase I will result in abrogation of tumor growth. To explore this hypothesis we will use a multidisciplinary approach consisting of three distinct but interdependent and complementary programs. Program #1 will design and synthesize peptidomimetics, transition state bisubstrate analogs and mechanism-based inhibitors of PGGTase I. Program #2 will perform structure activity relationship studies on these compounds to determine the requirements for selective inhibition of PGGTase I over the closely related enzymes PGGTase II and FTase in vitro and in whole cells. Program #2 will determine the ability of PGGTase I inhibitors to inhibit DNA synthesis, block cell cycle and promote apoptosis. Program #3 will determine the effects of the compounds on RhoA, Rac1, Cdc42, R-Ras and TC-21 oncogenic signaling, malignant transformation and invasion. Both Program #2 and 3 will address selectivity issues by using murine fibroblasts and human epithelial cells transformed with H-, K- and N-Ras, Src, Raf, EGFR and ErbB2. Feedback from Programs #2 and 3 will be used by Program #1 for lead optimization for second and third generation leads. The best compounds to emerge from these combined studies will then be evaluated by Program #2 for their ability to block the growth of tumors using a nude mouse xenograft model. Here the above transformed cells as well as human tumors with H-, N- or K-Ras mutations and tumors overexpressing Ras, ErbB2 or EGFR will be used. Future plans include advanced preclinical and clinical studies with our industrial and clinical partners. The work described in this NCDDG will enhance our understanding of the mechanism of action of GGTase I inhibitors, and ultimately result in novel anticancer drugs that will broaden the spectrum of human tumors that can be treated successfully.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067771-07
Application #
6376154
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (M1))
Program Officer
Lees, Robert G
Project Start
2000-09-18
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
7
Fiscal Year
2001
Total Cost
$647,885
Indirect Cost
Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Patel, R A; Liu, Y; Wang, B et al. (2014) Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 33:550-5
Vigil, Dominico; Kim, Tai Young; Plachco, Ana et al. (2012) ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res 72:5338-47
Li, Rongshi; Martin, Mathew P; Liu, Yan et al. (2012) Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J Med Chem 55:2474-8
Pireddu, Roberta; Forinash, Kara D; Sun, Nan N et al. (2012) Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm 3:699-709
Mitin, Natalia; Roberts, Patrick J; Chenette, Emily J et al. (2012) Posttranslational lipid modification of Rho family small GTPases. Methods Mol Biol 827:87-95
Patel, Ronil A; Forinash, Kara D; Pireddu, Roberta et al. (2012) RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res 72:5025-34
Neel, Nicole F; Martin, Timothy D; Stratford, Jeran K et al. (2011) The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery. Genes Cancer 2:275-87
Berndt, Norbert; Sebti, Saïd M (2011) Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors. Nat Protoc 6:1775-91
Cook, Danielle R; Solski, Patricia A; Bultman, Scott J et al. (2011) The ect2 rho Guanine nucleotide exchange factor is essential for early mouse development and normal cell cytokinesis and migration. Genes Cancer 2:932-42
Berndt, Norbert; Hamilton, Andrew D; Sebti, Saïd M (2011) Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11:775-91

Showing the most recent 10 out of 117 publications