Glasdegib

Identification

Summary

Glasdegib is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy.

Brand Names

Daurismo

Generic Name

Glasdegib

DrugBank Accession Number

DB11978

Background

Glasdegib, also known as PF-04449913, is a small-molecule hedgehog signaling inhibitor selected under the group of benzimidazoles. In early research, benzimidazoles attracted large interest as they represented a class of inhibitors with low molecular weight, potent inhibitory activity, and lacking unstable functionality.¹ 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 (AML).¹¹ Glasdegib targets cancerous cells by inhibiting the sonic hedgehog receptor smoothened (SMO), a transmembrane protein involved in the Hedgehog (Hh) signaling cascade.⁵ Aberrant of Hh signaling is one of the main pathophysiologies of AML, with observed overexpression or constitutive activation of SMO.^6,7 Although the efficacy of glasdegib monotherapy is limited, the landmark Phase 2 Bright AML 1003 trial showed a superior overall survival and complete response when glasdegib is combined with low dose cytarabine. Currently, the current gold standard of AML in older patients is still venetoclax with hypomethylation agents, new clinical combinations of glasdegib are being tested in hope of replacing venetoclax due to glasdegib's more favorable side effects profile.⁵

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Glasdegib (DB11978)

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Weight

Average: 374.448
Monoisotopic: 374.185509352

Chemical Formula

C₂₁H₂₂N₆O

Synonyms

• Glasdegib

External IDs

• PF 04449913
• PF-04449913
• PF-4449913

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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.⁹

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.¹⁰

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Acute myeloid leukemia	Regimen in combination with: Cytarabine (DB00987)	••••••••••••	•••••• •••••••		••••••• •••• ••••••
Used in combination to treat	Acute myeloid leukemia (aml)	Regimen in combination with: Cytarabine (DB00987)	••••••••••••	•••••	••••••••••••• •••• •••••••• ••••••••• ••••••••••••	••••••

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Contraindications & Blackbox Warnings

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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.⁹

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

Target	Actions	Organism
ASmoothened homolog	inhibitor	Humans

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 225 L.² The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.¹²

Protein binding

Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile.⁸

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

Hover over products below to view reaction partners

• Glasdegib
  • Glasdegib M1
  • Glasdegib M3
  • Glasdegib M11
  • Glasdegib M4
  • Glasdegib M2

Route of elimination

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.^4,12

Half-life

The reported half-life of glasdegib is of 17.4 hours.⁸

Clearance

The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.² The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.¹²

Adverse Effects

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Toxicity

Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985.¹²

In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus.¹²

Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay.¹²

Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose.

There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness.¹²

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Glasdegib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Glasdegib can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Glasdegib.
Abiraterone	The metabolism of Glasdegib can be decreased when combined with Abiraterone.
Abrocitinib	The serum concentration of Glasdegib can be increased when it is combined with Abrocitinib.

Food Interactions

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of glasdegib.
• Take at the same time every day.
• Take with or without food.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Glasdegib hydrochloride	4Y7R3PBO4V	1095173-64-0	OCHAAZGYSAHXOF-LJLRIERRSA-N
Glasdegib maleate	TH2EV99S4Z	2030410-25-2	VJCVKWFBWAVYOC-UIXXXISESA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Daurismo	Tablet, film coated	100 mg	Oral	Pfizer Europe Ma Eeig	2021-03-16	Not applicable
Daurismo	Tablet, film coated	25 mg	Oral	Pfizer Europe Ma Eeig	2021-03-16	Not applicable
Daurismo	Tablet, film coated	100 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2018-12-10	Not applicable
Daurismo	Tablet, film coated	100 mg	Oral	Pfizer Europe Ma Eeig	2021-03-16	Not applicable
Daurismo	Tablet	100 mg	Oral	Pfizer Canada Ulc	2020-08-10	Not applicable

Categories

ATC Codes

L01XJ03 — Glasdegib

• L01XJ — Hedgehog pathway inhibitors
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amides
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Benzene Derivatives
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Hedgehog Pathway Inhibitor
• Hedgehog pathway inhibitors
• Heterocyclic Compounds, Fused-Ring
• Highest Risk QTc-Prolonging Agents
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• QTc Prolonging Agents
• Smoothened Receptor Antagonists
• UGT1A9 Substrates

Chemical TaxonomyProvided by Classyfire

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 / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

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Substituents

Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzimidazole / Benzonitrile / Carbonitrile / Carbonyl group / Cyanide / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / N-phenylurea / Nitrile / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Piperidine / Tertiary aliphatic amine / Tertiary amine / Urea

show 15 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

K673DMO5H9

CAS number

1095173-27-5

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

1-[(2R,4R)-2-(1H-1,3-benzodiazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

SMILES

CN1CC[C@H](C[C@@H]1C1=NC2=CC=CC=C2N1)NC(=O)NC1=CC=C(C=C1)C#N

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. [Article]
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. [Article]
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. [Article]
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. [Article]
5. Iyer SG, Stanchina M, Bradley TJ, Watts J: Profile of Glasdegib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML): Evidence to Date. Cancer Manag Res. 2022 Aug 1;14:2267-2272. doi: 10.2147/CMAR.S195723. eCollection 2022. [Article]
6. Jamieson C, Martinelli G, Papayannidis C, Cortes JE: Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia. Blood Cancer Discov. 2020 Aug 11;1(2):134-145. doi: 10.1158/2643-3230.BCD-20-0007. eCollection 2020 Sep. [Article]
7. Terao T, Minami Y: Targeting Hedgehog (Hh) Pathway for the Acute Myeloid Leukemia Treatment. Cells. 2019 Apr 3;8(4):312. doi: 10.3390/cells8040312. [Article]
8. Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.
9. FDA news [Link]
10. NIH [Link]
11. FDA Approved Drug Products: Daurismo (glasdegib) oral tablets [Link]
12. FDA Approved Drug Products: Daurismo (glasdegib) oral tablets (March 2023) [Link]
13. EMA Assessment Report: Daurismo International non-proprietary name glasdegib [Link]
14. Pfizer Glasdegib product information [File]

External Links

PubChem Compound

25166913

PubChem Substance

347828300

ChemSpider

28518072

BindingDB

50385635

RxNav

2105845

ChEBI

145428

ChEMBL

CHEMBL2043437

ZINC

ZINC000068251434

Wikipedia

Glasdegib

FDA label

Download (572 KB)

MSDS

Download (24.6 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Acute Myeloid Leukemia	1
3	Completed	Treatment	Acute Myeloid Leukemia / Chronic Myelomonocytic Leukemia / Myelodysplastic Syndrome	1
3	Recruiting	Health Services Research	Soft Tissue Sarcoma	1
3	Recruiting	Treatment	Acute Myeloid Leukemia	1
3	Terminated	Treatment	Acute Myeloid Leukemia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	100 mg
Tablet	Oral	25 mg
Tablet, film coated	Oral	100 mg/1
Tablet, film coated	Oral	100 MG
Tablet, film coated	Oral	25 mg/1
Tablet, film coated	Oral	25 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8431597	No	2013-04-30	2028-06-29
US8148401	No	2012-04-03	2031-01-30
US10414748	No	2019-09-17	2036-04-13
US11168066	No	2021-11-09	2036-04-13

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	0.02 mg/ml (in the form of di-HCl monohydrate salt)	Munchhof M., et al. (2011). ACS Med Chem Lett.
logP	2.28	Munchhof M., et al. (2011). ACS Med Chem Lett.
Caco2 permeability	0.00000598	Munchhof M., et al. (2011). ACS Med Chem Lett.
pKa	6	Munchhof M., et al. (2011). ACS Med Chem Lett.

Predicted Properties

Property	Value	Source
Water Solubility	0.0469 mg/mL	ALOGPS
logP	2.68	ALOGPS
logP	2.28	Chemaxon
logS	-3.9	ALOGPS
pKa (Strongest Acidic)	11.39	Chemaxon
pKa (Strongest Basic)	6.67	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	96.84 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	108.26 m3·mol-1	Chemaxon
Polarizability	40.73 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0049000000-95adfc803c1d43ca30ba
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0395000000-e2bf38ac0737cad4bda1
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0189000000-56dfc6f45f475567ee71
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-002f-9581000000-f9bde29ab07cf8da4667
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-05ox-4938000000-f6d5c9edfc7d0b28d876
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014i-2922000000-38b506603028dba063be
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	179.29291	predicted	DeepCCS 1.0 (2019)
[M+H]+	181.68848	predicted	DeepCCS 1.0 (2019)
[M+Na]+	188.2357	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Smoothened homolog

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. [Article]

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Drug created at October 20, 2016 21:07 / Updated at February 20, 2024 23:54