Department of Medicinal Chemistry and Molecular Pharmacology Personnel - Richard A. Gibbs
Specialization: Medicinal and Bioorganic Chemistry, Synthesis and Mechanistic Evaluation of Anticancer Drugs
EducationB.A. - 1983 - Johns Hopkins University
Ph.D. - 1988 - University of California, Riverside
Postdoc - 1988-91 - Pennsylvania State University
Research: Medicinal and Bioorganic Chemistry, Synthesis and Mechanistic Evaluation of Anticancer Drugs
Chemical Probes of Protein Prenylation. It has recently been discovered that many proteins are modified by prenylation of a cysteine residue, followed by a specific proteolytic cleavage step and finally methylation. Prenylation and the two following steps are required for the membrane association and the biological activity of Ras proteins and many other key signal transduction proteins. This has led to intense interest in protein-farnesyl transferase (FTase) inhibitors as potential cancer chemotherapeutic agents, and such compounds are currently in human clinical trials. Our laboratory employs chemical biology approaches to address two key questions in the field of protein prenylation. We explore the substrate specificity of FTase, with the goal of developing potential isoprenoid-based inhibitors or modulators of protein prenylation. Secondly, we use synthetic isoprenoid analogues and labeled derivatives as probes of the biological function of protein prenylation. In more recent work, we are using our synthetic knowledge in the area of isoprenoids to develop inhibitors of the proteolytic cleavage and methylation steps.
We have developed a new stereospecific route to isoprenoids to synthesize novel, specifically substituted analogues of FPP, the isoprenoid substrate of FTase. This program led to the development of a series of potent inhibitors of FTase. We have demonstrated that certain farnesol analogues are potent inhibitors of the growth of certain human tumor cells in vitro. In a collaborative effort with the Borch laboratory here in MCMP, we are synthesizing prodrug variants of these compounds, in an attempt to enhance their in vivo activity. There are preliminary indications that these analogues may exert their effects through a novel mechanism - the selective modulation of the prenylation of a subset of prenylated proteins. Efforts to determine their mechanism of action are underway, in collaboration with the Harrison laboratory in MCMP.
A second active area of interest concerning protein prenylation has been the function of this modification - how does it target the attached protein to the appropriate cellular location? We have used the farnesylated a-factor mating peptide produced by Saccharomyces cerevisiae as a model system to evaluate the role of the prenyl group in the targeting of the prenylated protein to the proper position inside the cell and thus its biological activity. We have demonstrated that a) a-factor analogues with modified farnesyl groups exhibit a wide range of biological activities and b) the biological activities of these peptides do not correlate with their affinity for model lipid bilayers. These investigations are now being expanded into the realm of mammalian prenylated proteins. Specifically, we are now looking at the ability of prenylcysteine derivatives to bind to rhoGDI, and thus block the interaction of this protein with Rho proteins, which are key mediators of metastatic tumor growth. This work, along with other biological studies, is carried out with collaborators at Wayne State University.
Our laboratory has developed a general synthetic route to carbon-13 labeled farnesyl derivatives. In collaborative studies, we are using solid-state NMR methods and our carbon-13 labeled farnesyl analogues as probes for the conformation of the farnesyl moiety bound in various protein and membrane environments. Understanding the conformations of the prenyl moiety in different environments will help us to design better inhibitors of FTase and other related enzymes and receptors, and will also provide us with a deeper understanding of the biological function of protein prenylation. We have also synthesized prenylated peptides that have been used in structural studies by our collaborators at Scripps to develop a deeper understanding of the interaction of prenylated Rab proteins and the prenyl-binding protein RabGDI.
Our most recent efforts have been directed toward the development of inhibitors of the enzymes Icmt and RCE1. These two enzymes process Ras after its farnesylation by FTase, and very recent evidence has indicated that they are also potential anti-cancer targets. These studies are in collaboration with the Hrycyna laboratory in the Chemistry Department here at Purdue.
Gibbs lab, December 2004, left to right: seated - Brian Henriksen (Ph D 2005; current address - Barbas Laboratory, Scripps), Michelle Maynor, Animesh; kneeling - Amanda Krzysiak; standing - Rich Gibbs, Jimmy Donelson, Surya De, Laurel Royer, Sarah Reigard and Andrew Placzek
Yu An, Ying Shao, Christelle Alory, Jeanne Matteson, Toshi Sakisaka, Wei Chen, Richard A. Gibbs, Ian A. Wilson,* and William E. Balch* "Geranylgeranyl Switching Regulates GDI-Rab GTPase Recycling." Structure 2003, 11, 347-357.
This record was last updated on Aug 19, 2013 at 3:56 PM