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Angew Chem Int Ed Engl. 2019 Nov 4;58(45):16314-16319. doi: 10.1002/anie.201910124. Epub 2019 Sep 26.

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

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Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, 600 16th Street, San Francisco, CA, 94143, USA.


Here we report the design, synthesis, and 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, immunophilin, and the ligand. The recruitment of cyclophilin A to GTP-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 a promising therapeutic strategy for Ras-driven cancers.


Ras; cancer; dimerization; drug design; immunophilin


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