In vitro: Treatment with ROC-325 triggers all of the hallmark features of autophagy inhibition including the accumulation of autophagosomes with undegraded cargo, an increase in lysosomal membrane permeability, deacidification of lysosomes, and elevated LC3B, p62, and cathepsin D expression. In vitro treatment of a panel of human AML cell lines and normal human bone marrow progenitors demonstrate that ROC-325 diminishes AML cell viability (IC50 range 0.7-2.2 µM), antagonizes clonogenic survival, and induces apoptosis in a manner that is therapeutically selective.
In vivo: ROC-325 is well tolerated and no notable toxicities are observed other than a modest, non-significant reversible reduction in mean body weight. Oral administration of ROC-325 to mice bearing RCC xenografts is well tolerated and yields dose-dependent inhibition of tumor growth that is significantly more efficacious than a higher dose of HCQ.
| Cell Experiment | |
|---|---|
| Cell lines | RCC cells |
| Preparation method | RCC cells were treated with ROC-325 for 24 h and harvested for imaging. Briefly, sections were cut in an LKB Ultracut microtome (Leica), stained with uranyl acetate and lead citrate, and examined in a JEM 1230 transmission electron microscope. |
| Concentrations | 1 μM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | Mice |
| Formulation | water |
| Dosages | 25, 40, and 50 mg/kg |
| Administration | p.o. |
| Molecular Weight | 503.06 |
| Formula | C28H27ClN4OS |
| CAS Number | 1859141-26-6 |
| Solubility (25°C) | 4 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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