MK-4101 is a novel SMO antagonist of the Hedgehog Pathway. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1 MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. MK-4101 inhibits Hh signaling both in a reporter gene assay in an engineered mouse cell line (Gli_Luc) with IC50 = 1.5 µM and in human KYSE180 oesophageal cancer cells with an IC50 = 1 µM.
MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1(+/-) mice. MK-4101 could be administered orally, showing a good bioavailability (F ≥ 87 %) with low-to-moderate plasma clearance in mice and rats. Moreover, it was well absorbed, and mainly excreted into the bile.
| Cell Experiment | |
|---|---|
| Cell lines | BCC (basal cell carcinoma) cells |
| Preparation method | BCC cells are treated with MK-4101(10 μM) for 72 h and cell cycle is analyzed by FACS monitoring EdU incorporation. |
| Concentrations | 10 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | C57bl/6 mice or Sprague-Dawley rats |
| Formulation | 0.5% methylcellulose in deionized water |
| Dosages | 40 or 80 mg/kg once a day; 80 mg/kg twice a day |
| Administration | oral administration |
| Molecular Weight | 493.47 |
| Formula | C24H24F5N5O |
| CAS Number | 935273-79-3 |
| Solubility (25°C) | DMSO: ≥ 60 mg/mL |
| 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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