A New and General Method of Drug Development: Surface borrowing. An understanding of the mechanism of action of cyclosporin A, FK506 and rapamycin lead us to a new approach to drug development. Many therapeutic targets have been unassailable because they use a large surface area to interact with their targets and bring about a biologic function. Conventional drugs are too small to inhibit these large, somewhat plastic and refined protein interactions. To circumvent this problem we have developed a method in which a small molecule drug candidate borrows the surface area of an endogenous protein to create a composite drug-protein surface that then binds a protein target (see below). Roger Breisiwitz developed this method in the lab by making molecules that fused the FKBP binding entity of FK506 with an SH2-domain binding molecule. This resulted in enhanced affinity providing a proof-of-concept experiment (PNAS 1999). We are working with Tom Wandless's lab in the Chemistry Department to continue development of this class of molecules. Ultimately, we would like to combine this approach with genomic methods for finding protein-protein interactions and chemical diversity approaches for finding small molecule binders to proteins (see SL Schreiber web page) to develop inhibitors to explore biologic processes and develop drugs to now unassailable targets.