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
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