Discovery
Our Proprietary Technology Isolates Promising Candidates
Sunesis' discovery platform is anchored by our proprietary Tethering technology. Tethering allows us to screen drug fragments based on binding properties rather than function, which allows us to potentially identify compounds that may not be discovered through conventional methods of drug discovery. We believe that this capability allows us to efficiently design drug candidates that bind to sites or regions on a specific protein not readily accessed by other discovery methods. Sunesis has integrated Tethering with other state-of-the-art methods including structure-based design and functional screening.
Tethering and Selective Protein Kinase Inhibitors
Although it can be applied to a wide variety of targets, Tethering is ideally suited for identifying highly selective inhibitors of protein kinases. Kinases represent a major class of potential targets in oncology as they play essential roles in many of the biological pathways that drive tumor survival and growth. Many kinase inhibitors occupy a structurally conserved binding site and therefore inhibit multiple targets.
Tethering allows us to build inhibitors to structurally variable regions of the active site, thereby enabling us to find molecules that will only bind to a small subset of kinases. We have even been able to dissect the multiple pathways controlled by a central kinase by finding molecules that only inhibit a single pathway by binding to a unique state of the enzyme responsible for that pathway.
Having this discovery capability allows us to test specific hypotheses both preclinically and clinically. Our discovery platform has been successfully used to build our internal pipeline and to enable discovery-based collaborations with corporate partners.
Step 1. Through Tethering, we add a reversible chemical link known as a disulfide bond to stabilize the binding of a fragment to the target protein. To do so, we place a sulfur-containing amino acid called a cysteine, or use an existing cysteine, on the surface of the protein and screen the protein against our collection of sulfur-containing fragments.
Step 2. Fragments that bind near the cysteine form disulfide bonds with the protein, increasing the weight of the protein and allowing the detection of the fragment by mass spectrometry. Because of the equilibrium of the disulfide bond formation, Tethering can discriminate weakly bound fragments from those that have no intrinsic binding affinity to the protein.
Step 3. We create drug-like compounds by combining multiple fragments. For example, we use a process called Tethering with extenders to combine fragments. In Tethering with extenders, we use an initial fragment that binds to the target protein (which can be derived from Tethering or derived from compounds that are known to bind to the protein) as a basis for making an extender. The protein is modified with the extender and the extender is used to identify a companion fragment that occupies a neighboring site.
Step 4. The initial and companion fragments are combined into a single molecule and the attachment to the protein is removed. This ultimately generates a soluble drug-like compound that can be optimized using other approaches such as medicinal chemistry.
