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.
||BCC (basal cell carcinoma) cells
||BCC cells are treated with MK-4101(10 μM) for 72 h and cell cycle is analyzed by FACS monitoring EdU incorporation.
||C57bl/6 mice or Sprague-Dawley rats
||0.5% methylcellulose in deionized water
||40 or 80 mg/kg once a day; 80 mg/kg twice a day
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
|Body Surface Area (m2)
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by
||Animal B Km
|Animal A Km
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
||DMSO: ≥ 60 mg/mL
MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma.
Filocamo G, et al. Mol Cancer Ther. 2016 Jun;15(6):1177-89. PMID: 26960983.