SOUTH SAN FRANCISCO, Calif., March 12 /PRNewswire/ -- Sunesis Pharmaceuticals, Inc. announced today research findings in two peer-reviewed publications demonstrating that the Company's fragment-based discovery technology, "Tethering," can identify small molecule drug leads that other techniques, such as high-throughput screening and structure-based design, may be unable to find. An article published online on March 11, 2003 by the Journal of the American Chemical Society (JACS) provides details about the Company's discovery of the most potent small molecule antagonist of a cytokine receptor interaction in its Interleukin-2 (IL-2) program. A second article in the February 18, 2003 issue of the Proceedings of the National Academy of Sciences (PNAS) illustrates the role of Tethering in identifying dynamic, adaptive regions of IL-2 that can provide additional binding sites for small molecule drug discovery.
"As reported in the JACS article, Tethering allowed us to rapidly progress from a low-affinity, small molecule antagonist to one that showed a 50-fold enhancement in potency," stated James Wells, Ph.D., President and Chief Scientific Officer of Sunesis. "These results represent the first example of a high-affinity ligand for this target, and more generally demonstrate the possibility of protein-protein interactions as small molecule targets. By merging Tethering hits with previously identified pharmacophores, our scientists are able to find novel leads for many high-value enzyme targets and protein-protein interfaces." To date, the only commercially approved inhibitors of cytokine targets, such as IL-2, are protein-based injectables.
In addition, as reported in the PNAS study, the Company's scientists found adaptive sites in the target protein that are not evident upon inspection of x-ray crystal structure data of the native protein. They report that the IL-2 protein surface changed its conformation in the presence of tethered fragments. Dr. Wells commented, "These observations underscore the value and potential of an empirical process like Tethering to probe for adaptive binding sites on a target. Traditional structure-based approaches often do not provide sufficient insight for progressing potent leads against these more challenging but highly relevant disease targets."
The title of the JACS article is "Discovery of a Potent Small Molecule IL-2 Inhibitor Through Fragment Assembly." The second article, in PNAS, is entitled, "Binding of small molecules to an adaptive protein-protein interface."
Technology Overview
Sunesis' technology platform reliably generates novel hits against challenging targets by identifying binding ligands that other techniques such as high-throughput screening are too insensitive to find. Sunesis scientists screen libraries of fragments, fundamental building blocks of oral therapeutics, against validated targets that have been resistant to small molecule discovery. The basis for this approach is Tethering, a process in which the target selects fragments with binding affinity for a specific region on the target surface. By discovering drugs in pieces, Sunesis can efficiently search a chemical diversity space equivalent to hundreds of millions of compounds. Sunesis is using Tethering to discover oral therapeutics addressing a range of high-value enzyme targets and protein- protein interfaces, including cytokines, integrins, kinases, phosphatases, and proteases.
About Sunesis
Sunesis is a leading discovery-based pharmaceutical company that applies its breakthrough fragment-based technologies to create superior oral therapeutics for the most challenging and important disease targets. Sunesis is building a pipeline of innovative therapeutics addressing major diseases through internal development and selective partnering. |
