MK-4101

MK-4101 is a Smoothened (SMO) antagonist (IC₅₀ of 1.1 µM for 293 cells ) and also a potent inhibitor of the hedgehog pathway (IC₅₀ of 1.5 µM for mouse cells; IC₅₀ of 1 µM for KYSE180 oesophageal cancer cells). MK-4101 has robust antitumor activity that inhibits tumor cell proliferation and induces extensive apoptosis^[1]. IC50 & Target: IC50: 1.1 µM (293 cells ); 1.5 µM (mouse cells); 1 µM (KYSE180 oesophageal cancer cells)^[1] In Vitro: MK-4101 inhibits Hh signaling both in a reporter gene assay in an engineered mouse cell line with an IC₅₀ of 1.5 µM, and in human KYSE180 oesophageal cancer cells with an IC₅₀ of 1 µM. MK-4101 displaces a fluorescently-labeled cyclopamine derivative from 293 cells expressing recombinant human SMO with an IC₅₀ of 1.1 µM, implying that the compound binds to SMO. MK4101 also inhibits the proliferation of medulloblastoma cells derived from neonatallyirradiated Ptch1^-/+ mice in vitro with an IC₅₀ of 0.3 µM^[1].
MK-4101 (10 µM; 60 hours, 72 hours; medulloblastoma or BCC cells) treatment shows cell cycle arrest with a nearly complete disappearance of the S phase subpopulation, a prominent increase of the G1 population and, to a minor extent, of the G2 population^[1].
MK-4101 (10 µM; medulloblastoma or BCC cells) treatment significantly reduces cyclin D1 protein and accumulation of cyclin B1 protein^[1]. In Vivo: MK-4101 (40-80 mg/kg; oral administration; for 3.5 weeks; CD1 nude female mice) treatment shows tumor growth inhibition (40 and 80 mg/kg ) and tumor regression at the highest dose (80 mg/kg). MK-4101 treatment shows a dose-dependent down-regulation of Gli1 mRNA. The maximum effect for tumor inhibition and hedgehog pathway downregulation is achieved at 80 mg/kg^[1].