MK-4101

SKU: orb1223600

Description

A novel potent, orally bioavailable and brain penetrating Hedgehog pathway (Hh) inhibitor that inhibits Smoothened (Smo) with IC50 of 1.1 uM; inhibits Hh signaling in a reporter gene assay in cancer cells with IC50 of 1-1.5 uM, also inhibited the proliferation of medulloblastoma cells derived from neonatally irradiated Ptch1 /+ mice in vitro with IC50 of 0.3 uM; demonstrate a robust antitumor activity against Hh-driven tumors in vivo, shows potentiation for the treatment of medulloblastoma and BCC.Brain Cancer Preclinical(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.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.MK-4101 (10 μM; medulloblastoma or BCC cells) treatment significantly reduces cyclin D1 protein and accumulation of cyclin B1 protein.(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.

Key Properties

• CAS Number: 935273-79-3
• MW: 493.4723
• Purity: >98% (HPLC)
• Formula: C₂₄H₂₄F₅N₅O
• SMILES: CN1C(=NN=C1C23CCC(CC2)(CC3)C4=NOC(=N4)C5CC(C5)(F)F)C6=CC=CC=C6C(F)(F)F
• Target: Smoothened (Smo)
• Solubility: 10 mM in DMSO

Bioactivity

• 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. Animal model: 5-weeks old CD1 nude female mice with medulloblastoma/BCC cells. Dosage: 40 or 80 mg/kg once a day, 80 mg/kg twice a day. Administration: Oral administration; for 3.5 weeks. Result: Showed tumor growth inhibition (40 and 80 mg/kg) and tumor regression at the highest dose (80 mg/kg).
• 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. 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. MK-4101 (10 μM; medulloblastoma or BCC cells) treatment significantly reduces cyclin D1 protein and accumulation of cyclin B1 protein. Cell Cycle Analysis Cell line: Medulloblastoma or BCC cells. Concentration: 10 μM. Incubation time: 60 hours, 72 hours. Result: Showed cell cycle arrest. Western blot analysis. Cell line: Medulloblastoma or BCC cells. Concentration: 10 μM. Incubation time: Result: Significant reduction of cyclin D1 protein and accumulation of cyclin B1 protein.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

MK 4101 | MK4101

Quick Database Links

Gene Symbol

Smoothened (Smo)