Development of Caspase Inhbitors for Arthritis

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to apply a unique and powerful "extended tethering" technology to discover novel therapeutics for the treatment: of arthritis. Small molecule caspase-1 inhibitors represent a new class of arthritis therapeutics with the advantages of oral availability and decreased toxicity. Covalent tethering, a technology developed at Sunesis Pharmaceuticals involves a "screen-then-link" process that allows a greater survey of chemical diversity space than is achievable using the large compound libraries typically screened by pharmaceutical firms. A variation of this approach, known as extended tethering identified a high potency cell-active caspase-1 inhibitor during Phase I. Extended tethering is particularly powerful for enzyme targets such as caspase-l that contain an active site cysteine residue and for which active site binding determinants are well characterized. Moreover, extended tethering provides not only an efficient means of ligand discovery but also a direct path to lead optimization since the target protein is used as a template for the construction of its: own inhibitor. Our Phase II proposal capitalizes on the promising caspase-1 inhibitor identified by extended tethering in Phase I and proposes to carry it forward through lead optimization and to pre-clinical development.