Single-Step Synthesis of Cell-Permeable Protein Dimerizers That Activate Signal Transduction and Gene Expression

Abstract

The one-step "dimerization" (with loss of ethylene) of the immunosuppressant FK506 by olefin metathesis has been used to create new chemical inducers of dimerization (CIDs). These small-molecule protein dimerizers are shown to activate signal transduction pathways and gene transcription at low concentrations in mammalian cells. Their ease of synthesis provides ready access to reagents of widespread utility in studies of the cellular functions of proteins.

First Preparation of Spacer-Linked Cyclic Neooligoaminodeoxysaccharides

“…This observation contrasts some of the work published in this field. For example, the immunosuppressive natural product FK506 [26] was successfully homodimerized. Also the ring-closing metathesis of the disaccharide subunit of tricolorin A described by F¸rstner and co-workers was achieved in the presence of free alcohol groups.…”

Receptor-Dependence of the Transcription Read-Out in a Small-Molecule Three-Hybrid System

“…[5] There are reports, most notably with the a-keto-pipecolyl-amide FK506 analogues, where the linker strongly affects the levels of transcription activation. [9,22,23] Thus, we wanted to compare the activity of the DHFR proteins with Dex ± Mtx CIDs with different chemical linkers. Work with the two-hybrid system for detecting protein ± protein interactions has shown that the nature of the protein chimeras can dramatically influence the activity of the reconstituted transcriptional activator.…”

Recent Advances in Alkene Metathesis

“…As the reaction becomes more selective, CM steps are ever more frequently finding their way into total syntheses of natural products and their derivatives [73].…”