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Purity: ≥98%
MK-4101 is a novel, potent and selective SMO inhibitor/antagonist of the Hedgehog (Hh) signaling pathway. MK-401 has the potential for the treatment of medulloblastoma and BCC (Basal Cell Carcinoma) as it is highly active against these cells. MK-4101 inhibits Hh signaling both in a reporter gene assay in an engineered mouse cell line (Gli Luc) with IC50 of 1.5 µM and in human KYSE180 oesophageal cancer cells with an IC50 of 1 µM. Furthermore, MK-4101 displaced a fluorescently-labeled cyclopamine derivative from 293 cells expressing recombinant human SMO with an IC50 of 1.1 µM. MK-4101 arrests cells in G1 and G2 phases. Beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1(+/-) mice.
| Targets |
MK-4101 is a potent inhibitor of the Hedgehog (Hh) signaling pathway and acts as a novel SMO (Smoothened) antagonist; it exerts the maximum inhibitory effect on Gli1 (a key downstream effector of the Hh pathway). No IC50, Ki, or EC50 values for these targets (SMO or Gli1) were described in the literature. [1]
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| ln Vitro |
MK-4101 suppresses Hh signaling in human KYSE180 oesophageal cancer cells at an IC50 of 1 µM and in a reporter gene test using an engineered mouse cell line with an IC50 of 1.5 µM. With an IC50 of 1.1 µM, MK-4101 clears 293 cells expressing recombinant human SMO, suggesting that the molecule binds to SMO. It also displaces a fluorescently-labeled cyclopamine derivative. With an IC50 of 0.3 µM, MK4101 also prevents the growth of medulloblastoma cells obtained from neonatally irradiated Ptch1-/+ mice in vitro[1]. Treatment of MK -4101 (10 µM; 60 hours, 72 hours; medulloblastoma or BCC cells) results in cell cycle arrest with almost no S phase subpopulation remaining, a significant rise in the G1 population, and a little increase in the G2 population[1]. Treatment with MK-4101 (10 µM; medulloblastoma or BCC cells) dramatically decreases the accumulation of cyclin B1 protein and the cyclin D1 protein[1].
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| ln Vivo |
Tumor growth inhibition is shown at 40 and 80 mg/kg of MK-4101 (oral administration; 3.5 weeks; CD1 nude female mice) and tumor regression is observed at the highest dose (80 mg/kg). Gli1 mRNA is dose-dependently down-regulated in response to MK-4101 therapy; 80 mg/kg produces the greatest tumor inhibition and hedgehog pathway down-regulation[1].
1. Animal model: Neonatally irradiated Ptch1(+/-) mice were used as a model of Hh-dependent tumors (medulloblastoma and basal cell carcinoma, BCC). [1] 2. Antitumor activity against transplanted tumors: MK-4101 exhibited robust antitumor activity against transplanted Hh-dependent tumors. [1] 3. Antitumor activity against primary tumors: MK-4101 was highly efficacious against primary medulloblastoma developing in the cerebellum and primary BCC developing in the skin of Ptch1(+/-) mice. [1] 4. Mechanism of antitumor action: The antitumor effect of MK-4101 was achieved through two key mechanisms: (i) inhibition of tumor cell proliferation; (ii) induction of extensive apoptosis in tumor cells. Additionally, MK-4101 modulated the gene expression profile of tumors: it targeted the Hh pathway by maximally inhibiting Gli1, induced deregulation of the cell cycle, blocked DNA replication in tumors, and significantly deregulated genes involved in the IGF (Insulin-like Growth Factor) and Wnt signaling pathways—suggesting that the interplay among Hh, IGF, and Wnt pathways is crucial for Hh-dependent tumorigenesis. [1] |
| Cell Assay |
Cell Cycle Analysis[1]
Cell Types: Medulloblastoma or BCC cells Tested Concentrations: 10 µM Incubation Duration: 60 hrs (hours), 72 hrs (hours) Experimental Results: demonstrated cell cycle arrest. Western Blot Analysis[1] Cell Types: Medulloblastoma or BCC cells Tested Concentrations: 10 µM Incubation Duration: Experimental Results: Significant reduction of cyclin D1 protein and accumulation of cyclin B1 protein. |
| Animal Protocol |
Animal/Disease Models: 5-weeks old CD1 nude female mice with medulloblastoma /BCC cells[1]
Doses: 40 or 80 mg/kg one time/day, 80 mg/kg twice a day Route of Administration: Oral administration; for 3.5 weeks Experimental Results: demonstrated tumor growth inhibition (40 and 80 mg/kg ) and tumor regression at the highest dose (80 mg/kg). MK-4101 was administered orally to neonatally irradiated Ptch1(+/-) mice (used to model Hh-dependent medulloblastoma and BCC). No details on drug dissolution formula, dosage form, administration frequency, or specific dosage were described in the literature. [1] |
| References | |
| Additional Infomation |
1. Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is associated with the pathogenesis of a variety of cancers, including medulloblastoma and basal cell carcinoma (BCC)—both of which are targets of MK-4101. [1] 2. Drug properties: MK-4101 is a novel oral compound. [1] 3. Therapeutic potential: Preclinical studies have shown that MK-4101 offers a new therapeutic opportunity for Hh-driven cancers. [1] 4. Significance of combination therapy: The discovery that MK-4101 can regulate genes in the IGF and Wnt signaling pathways provides useful information for developing combination therapies with drugs that synergize with the oncogenic activity of the Hh pathway. [1]
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| Molecular Formula |
C24H24F5N5O
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| Molecular Weight |
493.47
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| Exact Mass |
493.19
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| CAS # |
935273-79-3
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| Related CAS # |
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| PubChem CID |
16222379
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
606.1±65.0 °C at 760 mmHg
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| Flash Point |
320.4±34.3 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.654
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| LogP |
4.58
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
35
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| Complexity |
779
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1C(C2N(C)C(C34CCC(CC3)(C3N=C(C5CC(F)(F)C5)ON=3)CC4)=NN=2)=CC=CC=1)(F)F
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0265 mL | 10.1323 mL | 20.2647 mL | |
| 5 mM | 0.4053 mL | 2.0265 mL | 4.0529 mL | |
| 10 mM | 0.2026 mL | 1.0132 mL | 2.0265 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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