Engineering small molecule specificity in nearly identical cellular environments

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Abstract

Methotrexate (MTX), an inhibitor of dihydrofolate reductase, was tethered to an FKBP12 ligand (SLF), and the resulting bifunctional molecule (MTXSLF) potently inhibits either enzyme but not both simultaneously. MTXSLF is cytotoxic to fibroblasts derived from FKBP12-null mice but is detoxified 40-fold by FKBP12 in wild-type fibroblasts. These studies demonstrate that non-target proteins in an otherwise identical genetic background can be used to predictably regulate the biological activity of synthetic molecules.

Graphical abstract

Differential expression of FKBP12 in mouse embryonic fibroblasts demonstrates selective detoxification of MTXSLF, a small molecule that binds either FKBP12 or DHFR but not both enzymes simultaneously.

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Acknowledgments

We thank Hank Bayle, Joe Arron, and the Crabtree lab for advice and materials, and Laura Banaszynski for valuable discussions. This research was supported by the NIH (GM 068589), and M.A.S. was supported by the Stanford NIH Medical Scientist Training Program.

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