Gcsf Sb 247464

SB 247464 was identified in a high-throughput, cell-based screen that detects compounds that activate the G-CSFR (36). A moderately sized library of organic compounds was screened against a cell line that expressed a functional murine G-CSFR using a signal transducer and activator of transcription (Stat)-luciferase protein reporter gene. SB 247464 was 30% as effective as G-CSF at a 1 |M concentration in the luciferase assay and displayed a biphasic dose-response curve. In terms of its ability to stimulate the proliferation of normal murine hematopoietic cells, SB 247464 was 25-80% as effective as G-CSF in murine progenitor cell (G-CFC) assays.

Scientists also demonstrated that SB 247464 phosphorylated the G-CSFR as well as Jakl, Jak3, Stat3, and Stat5 (36). Subcutaneous administration of 30 mg/kg of SB 247464 twice daily to normal mice resulted in a fourfold increase in blood neutrophil counts after 4 d. This effect was equivalent to 50 |g/kg of recombinant (r)G-CSF administered to normal mice in the same manner (Fig. 1). From a clinical perspective, SB 247464 was specific for the mouse G-CSFR and had no measurable activity in a number of human myeloid G-CSF-responsive cell lines. Thus, the ECD of the murine G-CSFR was required for SB 247464 activity. Although the precise mechanism of action of SB 247464 remains unclear, the data suggest that the compound binds to a region other than the G-CSF binding site and mediates dimerization of the G-CSFR.

Fig. 1. Granulopoietic activity of SB 247464 in vivo. Female BDF-1 mice were given twice-daily subcutaneous injections of either granulocyte colony-stimulating factor (G-CSF) (50 |ig/kg) in phosphate-buffered saline or SB 247464 dissolved in acidified H2O (pH 4.0). Control animals received only acidified H2O. After 4 d, blood was drawn, and the numbers of neutrophils were counted using a Tech-nicon hematology analyzer. Each bar represents the average of five mice; error bars show standard error of mean (SEM). Asterisks indicate neutrophil counts that differ from those in untreated controls with a p < 0.001 by analysis of variance (ANOVA). (Reproduced with permission from ref. 36. Copyright 1998 American Association for the Advancement of Science.)

Fig. 1. Granulopoietic activity of SB 247464 in vivo. Female BDF-1 mice were given twice-daily subcutaneous injections of either granulocyte colony-stimulating factor (G-CSF) (50 |ig/kg) in phosphate-buffered saline or SB 247464 dissolved in acidified H2O (pH 4.0). Control animals received only acidified H2O. After 4 d, blood was drawn, and the numbers of neutrophils were counted using a Tech-nicon hematology analyzer. Each bar represents the average of five mice; error bars show standard error of mean (SEM). Asterisks indicate neutrophil counts that differ from those in untreated controls with a p < 0.001 by analysis of variance (ANOVA). (Reproduced with permission from ref. 36. Copyright 1998 American Association for the Advancement of Science.)

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