The NCDDG overall long-term goal is to discover and to bring to advanced stages of preclinical development a series of GGTase I, RhoGEF and ROCK inhibitors for the treatment of human cancer. Accomplishment of this goal necessitates the involvement of several teams with expertise and strength in various disciplines and areas of drug discovery. Three interrelated and interdependent programs and 2 cores will work very closely together toward the above-mentioned common goal. Every step of our drug discovery process from design and synthesis of combinatorial libraries (Program 1), molecular modeling and virtual HTS (Core B), design of specific biochemical, molecular and cellular assays (Programs 2 and 3); to evaluation of antitumor activity in animals (Program 3) will be highly focused on the creation of pharmacological agents with the highest degree of selectivity towards human cancers with aberrantly activated Rho function. The 3 programs and 2 cores and their leaders are as follows: Program #1: Structure-based, rational design of GGTase I, RhoGEF and Rho kinase inhibitors. Program Leader: Andrew D. Hamilton, Ph.D., Irenee duPont Professor of Chemistry, Yale University. Program Co-leader: Nicholas Lawrence, Ph.D., Associate Professor of Chemistry, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida. Program #2: Validation of inhibitors of Rho GTPases for cancer treatment. Program Leader: Charming J. Der, Ph.D., Professor of Pharmacology, University of North Carolina at Chapel Hill Program Co-Leader: Adrienne D. Cox, Ph.D., Associate Professor of Radiation Oncology and Pharmacology, University of North Carolina at Chapel Hill Program #3: Biological and pharmacological evaluations of GGTase I, RhoGEF and Rho kinase inhibitors. Program Leader: Sai'd M. Sebti, Ph.D., Manuel and Adeline Garcia Professor of Drug Discovery and Director, Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute and Professor of Interdisciplinary Oncology, University of South Florida. Core A: Administration Core Leader: Said M. Sebti, Ph.D. Core B: High throughput screening and molecular modeling. Core Leader: John Sondek. Ph.D., Associate Professor of Pharmacology and Biochemistry & Biophysics, University of North Carolina at Chapel Hill Core Co-leader: Wayne C. Guida, Ph.D., Assistant Professor, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida and Professor of Biochemistry, Department of Chemistry, Eckerd College Core Co-leader: M. L. Richard Yip, Ph.D., Staff Scientist, High Throughput Screening Core, Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19CA067771-13S1
Application #
7431200
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (J1))
Program Officer
Ogunbiyi, Peter
Project Start
1997-09-01
Project End
2010-04-30
Budget Start
2007-05-23
Budget End
2008-04-30
Support Year
13
Fiscal Year
2007
Total Cost
$123,140
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
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
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
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
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