Disrupting Protein–Protein Interactions with Small Molecules
Tuesday, February 7, 2006
Presented by the Chemical Biology Discussion Group
Organizer: Andras Bauer and Brent Stockwell, Columbia University
Recent years have seen an increasing level of dialogue between chemists and biologists, the lines of communication consolidated by the availability of recombinant biotechnology tools for manipulating the chemical structure of genes, and the proteins they encode. This has led to an explosion of interdisciplinary activity at the chemistry/biology interface, now coined chemical biology. Meetings of this group provides a forum for lively discussion and for establishing connections, and perhaps collaborations, between chemists armed with novel technologies and biologists receptive to using these approaches to solve their chosen biological problem.
4:00 - 6:00: Presentations
Andras Bauer, Columbia University
Loren D. Walensky, Dana Farber Cancer Institute/Children's Hospital Boston, "Targeting Protein Interactions in Vivo Using Hydrocarbon-Stapled Peptide Helices."
Ramesh Shivdasani, Dana-Farber Cancer Institute, Harvard Medical School, "Chemical Targeting of Protein-Protein Interactions in Cancer Therapy."
"Targeting Protein Interactions in Vivo Using Hydrocarbon-Stapled Peptide Helices"
Loren D. Walensky
Protein interactions are fundamental to the regulation of biological control points that sustain cellular homeostasis. The BCL-2 family of proteins regulates apoptosis, or programmed cell death, through a complex network of protein-protein interactions that dictate cell fate. Indeed, a wide spectrum of human diseases directly results from faulty regulation of apoptosis, leading to premature cell death or unchecked cellular survival. Protein interaction among BCL-2 proteins is mediated through an alpha helical segment termed BH3, which functions as an essential death domain. Because natural peptides display evolutionarily-honed binding specificity, synthetic peptides of the BCL-2 family offer the potential to selectively disrupt or activate these "life-and-death" protein interactions. However, the utility of peptides as biological reagents and prototype therapeutics has been severely compromised by their lack of biologically-active structure, susceptibility to degradation, and difficulty entering cells. Our research focuses on developing and applying new approaches to chemically brace natural peptides so that their shape, and therefore their biological activity, can be restored. We applied a novel chemical strategy, termed "hydrocarbon-stapling", to generate a panel of BCL-2 peptides with improved pharmacologic properties. The stapled peptides proved to be helical, protease-resistant, and capable of entering and killing leukemia cells by activating their death pathway. When administered to mice with leukemia, a stapled BCL-2 peptide successfully blocked cancer growth and prolonged the lives of treated animals. Our ongoing work involves the development of a chemical toolbox of hydrocarbon-stapled peptides to study and target pathologic signaling pathways in human cancer.
"Chemical Targeting of Protein-Protein Interactions in Cancer Therapy"
Colorectal cancer is a major cause of death in the West and currently is treated by surgical intervention if detected early or with limited success by traditional chemotherapy in advanced disease. The distinct molecular events that underlie pathogenesis of this disease are known in some detail. We designed studies to screen chemical compounds that disrupt the interaction between two proteins, Tcf4 and beta-catenin, that form a critical oncogenic complex. Selected compounds interfered with formation or stability of Tcf4/beta-catenin complexes in multiple laboratory tests, including growth of colorectal cancer cells grown in tissue culture. Such compounds validate the strategy of targeting protein-protein