In vitro: DLBCL cells are exposed to 50 μM FX1 for 30 minutes. FX1 profoundly reduces recruitment of BCOR and SMRT to all 3 BCL6 target genes, but not at a negative control locus. There is little presence of SMRT at these loci in the BCL6-negative DLBCL cell line, which is not affected by FX1. The superior potency of FX1 versus 79-6 in disrupting BCL6 binding to SMRT is evident when these small molecules are compared head to head in quantitative ChIP assays in DLBCL cells after treatment with 50 μM FX1 for 6 hours. DLBCL cells are exposed to FX1 and mRNA is collect at 4 serial time points. FX1 almost invariantly induces significant derepression of these genes as compare with vehicle in 2 independent DLBCL cell lines.
In vivo: Spleens in FX1-treating mice are macroscopically indistinguishable from vehicle controls. Total B cell abundance measured by flow cytometry is unaffected by FX1. GC B cells (GL7+FAS+B220+) are significantly depleted by exposure to FX1. Splenic architecture is examined by IHC. Staining with B220 antibody reveals normal B cell follicular structures, whereas staining for the GC B cell-specific marker peanut agglutinin shows profound loss of GCs. The half-life is estimated to be approximately 12 hours. Finally, whether FX1 can induce toxic effects in mice is assessed. No signs of toxicity, inflammation, or infection are evident from H&E-stained sections of lung, gastrointestinal tract, heart, kidney, liver, spleen, and bone marrow of the fixed organs from mice treated with FX1 compare with vehicle.
| Cell Experiment | |
|---|---|
| Cell lines | DLBCL cells |
| Preparation method | Quantitative ChIP is performed in SUDHL-6 cells exposed to FX1 (black bars) or vehicle (white bars) in DLBCL cells using antibodies for BCL6, SMRT, BCOR, or IgG control to enrich for known BCL6 binding sites in the CD69, CXCR4, and DUSP5 loci, or a negative control region. |
| Concentrations | 50 μM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | SCID mice bearing SUDHL-6 xenografts |
| Formulation | 35% PEG-300, 5% Tween-80, 65% Dextrose 5% |
| Dosages | 50 mg/kg |
| Administration | i.p. |
| Molecular Weight | 368.82 |
| Formula | C14H9ClN2O4S2 |
| CAS Number | 1426138-42-2 |
| Solubility (25°C) | 30 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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