Richard Chamberlin
Chemistry
School of Physical Sciences
Phone: (949) 824-7089
Email: archambe@uci.edu
http://www.faculty.uci.edu/profile.cfm?faculty_id=4902
http://chem.ps.uci.edu/~archambe/
Richard Chamberlin
A major area of interest of Dr. Chamberlin is the design and synthesis of small molecules that modulate the activity of the important serine-threonine protein phosphatases PP1 and PP2A. Inhibitors such as the naturally occurring toxins okadaic acid, microcystin, and tautomycin have been the only available small molecule probes used by cell biologists to study the respective roles of PP1 and PP2A in cellular signaling pathways. Using these natural products as "lead" compounds, they are designing and synthesizing simplified analogues with improved selectivity or other valuable properties. For example, they have recently shown that highly truncated versions of microcystin and tautomycin retain nanomolar activities (albeit at significantly reduced levels compared to the parent toxins) and thus provide relatively easy-to-prepare scaffolds for exciting new studies of in vivo imaging of phosphatase trafficking via fluorescently labeled versions of the truncated compounds. They have also reported the first small molecule activator of PP1, which exerts its unusual activity by binding at the allosteric regulatory site on the protein.
Dr. Chamberlin also working on several collaborative projects with fellow CRI members to develop new types of anti-tumor compounds. Many labs have made substantial progress in the past several years in developing effective chemotherapeutic agents for the treatment of HIV infection, but there remains a substantial demand for new strategies. Their approach, in collaboration with Ed Robinson, is to employ computational ligand-based design in conjunction with combinatorial library synthesis to develop new HIV Integrase (IN) inhibitors based on the natural product IN inhibitor chicoric acid. They are also participants in a multi-investigator collaboration that targets the tumor suppressor protein p53, mutations of which appear in approximately half of all human cancers. With a combination of structural and computational data from collaborators, they have designed a first-generation moleclule that is predicted to bind to a number of inactive p53 mutants, thereby stabilizing the native structure and restoring function. Screening of combinatorial libraries by collaborators (Brachmann, Luecke) has produced an active compound that they have used as a lead to produce more soluble analogs, one of which has recently be shown (by NMR, Cocco) to bind to the p53 core domain. Finally, a collaboration with Wen-Hwa Lee is investigating the disruption of several protein-protein binding interactions, BRCA2-Rad51 and Hec1-Nek2, for breast cancer chemotherapy.
Selected Publications:
Gulledge, B. M., Aggen, J. B., Eng, H., Sweimeh, K., and Chamberlin, A. R. (2003). Microcystin analogues comprised only of Adda and a single additional amino acid retain moderate activity as PP1/PP2A inhibitors. Bioorg Med Chem Lett 13(17), 2907-11.
Hart, M. E., Chamberlin, A. R., Walkom, C., Sakoff, J. A., and McCluskey, A. (2004). Modified norcantharidins; synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity. Bioorg Med Chem Lett 14(8), 1969-73.
Charvat, T. T., Lee, D. J., Robinson, W. E., and Chamberlin, A. R. (2006). Design, synthesis, and biological evaluation of chicoric acid analogs as inhibitors of HIV-1 integrase. Bioorg Med Chem 14(13), 4552-67.
Tappan, E., and Chamberlin, A. R. (2008). Activation of protein phosphatase 1 by a small molecule designed to bind to the enzyme's regulatory site. Chem Biol 15(2), 167-74. |
