Synthesis and activity of bivalent FKBP12 ligands for the regulated dimerization of proteins

• Published in: Bioorganic & medicinal chemistry Vol. 6; no. 8; pp. 1309 - 1335
• Main Authors: Keenan, Terence, Yaeger, David R., Courage, Nancy L., Rollins, Carl T., Pavone, Mary Ellen, Rivera, Victor M., Yang, Wu, Guo, Tao, Amara, Jane F., Clackson, Tim, Gilman, Michael, Holt, Dennis A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.1998
• Subjects: Apoptosis - drug effects; Carboxylic Acids - chemical synthesis; Carboxylic Acids - pharmacology; Dimerization; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Humans; Immunophilins - metabolism; In Vitro Techniques; Inhibitory Concentration 50; Ligands; Piperidines - chemical synthesis; Piperidines - pharmacology; Proteins - metabolism; Structure-Activity Relationship; Tacrolimus Binding Proteins; Tumor Cells, Cultured
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(98)00125-4

The total synthesis and in vitro activities of a series of chemical inducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusion proteins has been demonstrated to have broad utility in biological research as well as potential medical applications in gene and cell therapies. The facility and flexibility of preparation make this new class of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein–protein interactions or protein localization. While some congeners possess potency comparable to or better than the first generation natural product-derived CID, FK1012, structure–activity relationships are complex and underscore the need for application-specific compound optimizations.