Identification

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Name
Glasdegib
Accession Number
DB11978
Type
Small Molecule
Groups
Approved, Investigational
Description

Glasdegib, also known as PF-04449913, is a small-molecule hedgehog signaling inhibitor selected under the group of the benzimidazoles. In early research, benzimidazoles attracted large interest as they represented a class of inhibitors with a low molecular weight, potent inhibitory activity and lacking unstable functionality. The great lipophilicity of this group of compounds brought interest to further modification. This analysis concluded that the presence of p-cyano ureas presented good physicochemical and pharmacokinetic properties from which glasdegib was developed.1

Glasdegib was developed by Pfizer Inc and approved on November 21, 2018, by the FDA for the treatment of Acute Myeloid Leukemia.6

Structure
Thumb
Synonyms
  • Glasdegib
External IDs
PF-04449913 / PF-4449913
Product Ingredients
IngredientUNIICASInChI Key
Glasdegib hydrochloride4Y7R3PBO4V1095173-64-0OCHAAZGYSAHXOF-LJLRIERRSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DaurismoTablet, film coated100 mg/1OralPfizer Laboratories Div Pfizer Inc2018-12-10Not applicableUs
DaurismoTablet, film coated25 mg/1OralPfizer Laboratories Div Pfizer Inc2018-12-10Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
K673DMO5H9
CAS number
1095173-27-5
Weight
Average: 374.448
Monoisotopic: 374.185509352
Chemical Formula
C21H22N6O
InChI Key
SFNSLLSYNZWZQG-VQIMIIECSA-N
InChI
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
IUPAC Name
3-[(2R,4R)-2-(1H-1,3-benzodiazol-2-yl)-1-methylpiperidin-4-yl]-1-(4-cyanophenyl)urea
SMILES
CN1CC[C@H](C[C@@H]1C1=NC2=CC=CC=C2N1)NC(=O)NC1=CC=C(C=C1)C#N

Pharmacology

Indication

Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy.7

Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults.8

Associated Conditions
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.2

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.2

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.7

Mechanism of action

Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor.1

The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce.3

TargetActionsOrganism
ASmoothened homolog
inhibitor
Humans
Additional Data Available
Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

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.2 The oral bioavailability of glasdegib is reported to be of 55%.1

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.2

The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.Label

Volume of distribution

Glasdegib reported volume of distribution in a dose of 50 mg is of 225 L.2

Protein binding

Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile.5

Metabolism

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.4

Route of elimination

From the administered dose of 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.4

Half life

The reported half-life of glasdegib is of 17.4 hours.5

Clearance

The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.2

Toxicity

Glasdegib is not mutagenic in bacterial reverse mutation assays and is not clastogenic in in vitro chromosome aberration assays. In fertility studies, glasdegib has the potential to impair reproductive function in males due to the production of testicular changes such as hypospermatogenesis.Label

Overdose by glasdegib starts at 640 mg/day and shows to present nausea, vomiting, dehydration, fatigue, and dizziness. In case of overdose, symptomatic treatment and ECG monitoring are advised.Label

The reported oral LD50 in rat of gladegib administered in triacetin is reported to be of 3000 mg/kg.9

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Glasdegib can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Glasdegib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Glasdegib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Glasdegib.
5-androstenedioneThe metabolism of Glasdegib can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Glasdegib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Glasdegib can be decreased when combined with 6-O-benzylguanine.
7-ethyl-10-hydroxycamptothecinThe metabolism of Glasdegib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Glasdegib.
AbataceptThe metabolism of Glasdegib can be increased when combined with Abatacept.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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    Evidence Level

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    Evidence Level

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Food Interactions
Not Available

References

Synthesis Reference

Munchhof MJ, Li Q, Shavnya A, et al. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2012;3(2):106-11.

General References
  1. Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT: Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. doi: 10.1021/ml2002423. eCollection 2012 Feb 9. [PubMed:24900436]
  2. Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, Onishi Y, Kobayashi M, Ikuta M, Chan G, Woolfson A, Ono C, Shaik MN, Fujii Y, Zheng X, Naoe T: Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017 Aug;108(8):1628-1633. doi: 10.1111/cas.13285. Epub 2017 Jun 19. [PubMed:28556364]
  3. Irvine DA, Copland M: Targeting hedgehog in hematologic malignancy. Blood. 2012 Mar 8;119(10):2196-204. doi: 10.1182/blood-2011-10-383752. Epub 2012 Jan 5. [PubMed:22223823]
  4. Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN: Metabolism, excretion and pharmacokinetics of [(14)C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017 Dec;47(12):1064-1076. doi: 10.1080/00498254.2016.1261307. Epub 2017 Jan 3. [PubMed:27866461]
  5. Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.
  6. FDA approvals [Link]
  7. FDA news [Link]
  8. NIH [Link]
  9. Pfizer Glasdegib product information [File]
External Links
PubChem Compound
25166913
PubChem Substance
347828300
ChemSpider
28518072
BindingDB
50385635
ChEMBL
CHEMBL2043437
Wikipedia
Glasdegib
FDA label
Download (572 KB)
MSDS
Download (24.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteer Study1
1CompletedBasic ScienceHealthy Volunteers3
1CompletedBasic ScienceHepatic Impairment1
1CompletedTreatmentMalignancies, Hematologic1
1CompletedTreatmentTumors, Solid1
1RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentGlioblastomas1
1, 2RecruitingTreatmentAcute, recurrent Myeloid Leukemia / Leukemia Acute Myeloid Leukemia (AML) / Refractory Acute Myeloid Leukemia1
1, 2RecruitingTreatmentSclerodermoid Chronic Graft-Versus-Host Disease (Disorder)1
2Active Not RecruitingTreatmentChronic Myelomonocytic Leukemia (CMML) / Myelodysplastic Syndromes (MDS)1
2CompletedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2RecruitingTreatmentAdult Acute Lymphoblastic Leukemia in Remission / Adult Acute Myeloid Leukemia in Remission / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Adult Acute Myeloid Leukemia1
2RecruitingTreatmentAdult Acute Myeloid Leukemia / Adult Myelodysplastic Syndrome / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Therapy-Related Acute Myeloid Leukemia1
2RecruitingTreatmentChronic Myelomonocytic Leukemia / Leukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome1
2TerminatedTreatmentPrimary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis1
3Not Yet RecruitingHealth Services ResearchSoft Tissue Sarcoma (STS)1
3RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral25 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8431597No2013-04-302028-06-29Us
US8148401No2012-04-032031-01-30Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)> 214 ºC'MSDS'
boiling point (°C)Decomposes at 214 ºC'MSDS'
water solubility0.02 mg/ml (in the form of di-HCl monohydrate salt)Munchhof M., et al. (2011). ACS Med Chem Lett.
logP2.28Munchhof M., et al. (2011). ACS Med Chem Lett.
Caco2 permeability0.00000598Munchhof M., et al. (2011). ACS Med Chem Lett.
pKa6Munchhof M., et al. (2011). ACS Med Chem Lett.
Predicted Properties
PropertyValueSource
Water Solubility0.0469 mg/mLALOGPS
logP2.68ALOGPS
logP2.28ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)11.39ChemAxon
pKa (Strongest Basic)6.67ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area96.84 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity108.26 m3·mol-1ChemAxon
Polarizability40.98 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-phenylureas. These are compounds containing a N-phenylurea moiety, which is structurally characterized by a phenyl group linked to one nitrogen atom of a urea group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
N-phenylureas
Direct Parent
N-phenylureas
Alternative Parents
Benzimidazoles / Benzonitriles / Aralkylamines / Piperidines / Imidazoles / Heteroaromatic compounds / Ureas / Trialkylamines / Nitriles / Azacyclic compounds
show 3 more
Substituents
N-phenylurea / Benzimidazole / Benzonitrile / Aralkylamine / Piperidine / Azole / Imidazole / Heteroaromatic compound / Urea / Tertiary aliphatic amine
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Wnt-protein binding
Specific Function
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought t...
Gene Name
SMO
Uniprot ID
Q99835
Uniprot Name
Smoothened homolog
Molecular Weight
86395.95 Da
References
  1. Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT: Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. doi: 10.1021/ml2002423. eCollection 2012 Feb 9. [PubMed:24900436]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN: Metabolism, excretion and pharmacokinetics of [(14)C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017 Dec;47(12):1064-1076. doi: 10.1080/00498254.2016.1261307. Epub 2017 Jan 3. [PubMed:27866461]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN: Metabolism, excretion and pharmacokinetics of [(14)C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017 Dec;47(12):1064-1076. doi: 10.1080/00498254.2016.1261307. Epub 2017 Jan 3. [PubMed:27866461]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da

Drug created on October 20, 2016 15:07 / Updated on May 01, 2019 13:22