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Purity: ≥98%
Glasdegib (formerly known as PF-04449913; PF4449913; PF04449913; PF-4449913; Daurismo) is a novel, potent, and orally bioavailable small-molecule inhibitor of Smoothened (Smo) in the Hedgehog (Hh) signaling pathway with potential antitumor activity. It is a drug that was authorized in 2018 to treat acute myeloid leukemia that has just been discovered. Smoothened (Smo) is inhibited by Glasdegib at a 5 nM IC50. Cellular development, differentiation, and repair are all significantly impacted by the Hh signaling pathway. Many forms of cancer have been shown to exhibit constitutive activation of the Hh pathway signaling. In a Ptch1+/-p53+/- allograft model, Glasdegib dramatically inhibits the growth of medulloblastoma at doses that also reduce the expression of the murine Shh target gene. When PF-04449913 is used in stromal co-culture experiments, FACS analysis shows a significant decrease in BC LSC relative to normal progenitors.
| Targets |
Smo ( IC50 = 4 nM )
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| ln Vitro |
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| Enzyme Assay |
Glasdegib, a novel potent small-molecule inhibitor with an IC50 of 5 nM, is an oral bioavailable inhibitor of Smoothened (Smo) in the Hedgehog (Hh) signaling pathway. It was previously known as PF-04449913. In cells, the Hh signaling pathway is essential for growth, differentiation, and repair. In many different kinds of cancer, constitutive activation of the Hh pathway signaling has been reported. In an allograft model with Ptch1+/-p53+/-, Glasdegib dramatically inhibits the growth of medulloblastoma at doses that also reduce the expression of the murine Shh target gene. When compared to normal progenitors, FACS analysis shows a significant reduction in BC LSC by PF-04449913 in stromal co-culture experiments.
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| Cell Assay |
BMS-354825 (50 nM), Glasdegib (PF-04449913) (1 μM), or a combination of these treatments are used to treat CD34+cells in BC CML or normal cells. The M2-10B4 (M2) and SL/SL (SL) mouse bone marrow stromal cell lines are plated 1:1 mixture at a final concentration of 100,000 cells/mL one day before being co-cultured with 10,000–20,000 CD34+BC CML or normal progenitors. At 14 days, progenitors are scored and FACS sorted into hematopoietic progenitor assays following a week of culture. Normal human hematopoietic stem and progenitor cells are evaluated for survival using the following methods: irradiated (20 Gray) OP9 (M2 clone) stromal cells are co-cultured with 50,000 human CD34+cord blood cells, vehicle, or Glasdegib (PF-04449913) in AlphaMEM with 20% Hyclone FBS, 1% pen strep glutamine, and supplemented with 50 ng/mL SCF, 10 ng/mL thrombopoietin, and 10 ng/mL Flt3. The results are recorded using weekly FACS analysis[1].
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. Metabolism / Metabolites After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. Biological Half-Life The reported half-life of glasdegib is of 17.4 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity
Elevations in serum ALT levels are common during glasdegib therapy, occurring in 31% of patients and rising above 5 times the upper limit of the normal range in 11%. Glasdegib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of hedgehog inhibitors, their potential for causing liver injury is not well defined. Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on glasdegib during breastfeeding. It is 91% bound to plasma proteins, so amounts in milk are likely to be low. With a half-life of 17.4 hours, it is likely to be eliminated from milk by 4 to 7 days after the last dose. However, the manufacturer recommends that breastfeeding be discontinued during glasdegib therapy and for at least 30 days after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. |
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| Additional Infomation |
Pharmacodynamics
In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib. |
| Molecular Formula |
C21H22N6O
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| Molecular Weight |
374.44
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| Exact Mass |
374.185
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| Elemental Analysis |
C, 67.36; H, 5.92; N, 22.44; O, 4.27
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| CAS # |
1095173-27-5
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| Related CAS # |
1095173-27-5; 2030410-25-2; 1095173-64-0 (HCl); 1352568-48-9 (2HCl)
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| PubChem CID |
25166913
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| Appearance |
White solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
633.4±55.0 °C at 760 mmHg
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| Flash Point |
336.9±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.686
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| LogP |
2.77
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
595
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C(NC1=CC=C(C#N)C=C1)N[C@H]2C[C@H](C3=NC4=CC=CC=C4N3)N(C)CC2
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| InChi Key |
SFNSLLSYNZWZQG-VQIMIIECSA-N
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| InChi Code |
InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1
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| Chemical Name |
1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
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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: ≥ 2.08 mg/mL (5.55 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 20.8 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: ≥ 2.08 mg/mL (5.55 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 20.8 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: ≥ 2.08 mg/mL (5.55 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 | 2.6707 mL | 13.3533 mL | 26.7065 mL | |
| 5 mM | 0.5341 mL | 2.6707 mL | 5.3413 mL | |
| 10 mM | 0.2671 mL | 1.3353 mL | 2.6707 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.
Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma
CTID: NCT03466450
Phase: Phase 1/Phase 2 Status: Completed
Date: 2024
A phase Ib/IIa pilot trial of the oral Hedgehog Signalling Inhibitor, Glasdegib, in Patients with sclerotic chronic graft-versus-host disease refractory to second-line treatment
CTID: null
Phase: Phase 1, Phase 2 Status: Completed
Date: 2017-09-28
 Selective shh inhibition reduces lsc burden in stromal co-cultures.J Transl Med.2015 Mar 21;13:98. |
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Shh inhibition induces cycling of dormant leukemic progenitors.J Transl Med.2015 Mar 21;13:98. |
PF-04449913 induced cell cycle activation enhances TKI sensitivity.J Transl Med.2015 Mar 21;13:98. |
GLI2 induces cell cycle arrest in leukemic progenitors.J Transl Med.2015 Mar 21;13:98. |
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SHH pathway deregulation in chronic myeloid leukemia progression.J Transl Med.2015 Mar 21;13:98. |
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