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Engineering small molecule specificity in nearly identical cellular environments.

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.

SUBMITTER: Sellmyer MA

PROVIDER: S-EPMC1949043 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Engineering small molecule specificity in nearly identical cellular environments.

Sellmyer Mark A MA Stankunas Kryn K Briesewitz Roger R Crabtree Gerald R GR Wandless Thomas J TJ

Bioorganic & medicinal chemistry letters 20070312 10

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 syn ...[more]

PMID: 17383876

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