Bifunctional Small Molecule Ligands of K-Ras Induce Its Association with Immunophilin Proteins

Abstract

Here we report the design, synthesis,a nd characterization of bifunctional chemical ligands that induce the association of Ras with ubiquitously expressed immunophilin proteins such as FKBP12 and cyclophilin A. We show this approach is applicable to two distinct Ras ligand scaffolds,and that both the identity of the immunophilin ligand and the linker chemistry affect compound efficacy in biochemical and cellular contexts.These ligands bind to Ras in an immunophilin-dependent fashion and mediate the formation of tripartite complexes of Ras,i mmunophilin, and the ligand. The recruitment of cyclophilin AtoGTP-bound Ras blocks its interaction with B-Raf in biochemical assays.Our study demonstrates the feasibility of ligand-induced association of Ras with intracellular proteins and suggests it as ap romising therapeutic strategy for Ras-driven cancers.

Bifunctional chemical probes inducing protein–protein interactions

“…homodimerization [17]. More recently, Shokat and colleagues developed bifunctional molecules that recruit the cancer target Ras in a tripartite complex with FKBP12 and cyclophilin A as a strategy to interfere with Ras activity and block its downstream signaling pathway [18].…”