MK-4101

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型强效、口服生物利用度和脑穿透性 Hedgehog 通路 (Hh) 抑制剂，可抑制 Smoothened (Smo)，IC50 为 1.1 uM。

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.

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.

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).

MK 4101 | MK4101

Wnt/Notch/Hedgehog

Smoothened (Smo)

Smoothened

Cancer

Brain Cancer

935273-79-3

493.4723

C24H24F5N5O

>98% (HPLC)

10 mM in DMSO

CN1C(=NN=C1C23CCC(CC2)(CC3)C4=NOC(=N4)C5CC(C5)(F)F)C6=CC=CC=C6C(F)(F)F

1,2,4-Oxadiazole, 5-(3,3-difluorocyclobutyl)-3-[4-[4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl]-

(-20℃)

With Ice Pack

≥ 2 years