SYNTHESIS AND ACTIVITY OF BIVALENT FKBP12 LIGANDS FOR THE REGULATED DIMERIZATION OF PROTEINS

The total synthesis and in vitro activities of a series of chemical in ducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusio n proteins has been demonstrated to have broad utility in biological r esearch as well as potential medical applications in gene and cell the rapies. The facility and flexibility of preparation make this new clas s of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein-protein in teractions or protein localization. While some congeners possess poten cy comparable to or better than the first generation natural product-d erived CID, FK1012, structure-activity relationships are complex and u nderscore the need for application-specific compound optimizations. (C ) 1998 Published by Elsevier Science Ltd. All rights reserved.