General
Preferred name
GLASDEGIB
Synonyms
PF-04449913 ()
PF 04449913 maleate ()
1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea ()
Glasdegib (PF-04449913) ()
PF-4449913 ()
PF-04449913 MALEATE ()
Daurismo ()
GLASDEGIB MALEATE ()
PF-04449913 ()
P&D ID
PD012458
CAS
1095173-27-5
2030410-25-2
Tags
available
drug
Approved by
FDA
First approval
2018
Drug indication
Solid tumour/cancer
Chronic myelomonocytic leukaemia
Drug Status
approved
investigational
Max Phase
4.0
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Glasdegib is a potent and orally active inhibitor of the hedgehog signalling pathway, acting as an antagonist of the class frizzled GPCR, smoothened (SMO) .
ROE
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.[A173872]
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.[L5080] 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.[L4832]
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.[A173857] 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.[A173857] 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.[L5080]
HALF-LIFE
The reported half-life of glasdegib is of 17.4 hours.[T367]
MOA
Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor.[A40310] 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.[A173860]
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.[FDA 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.[FDA label] The reported oral LD50 in rat of gladegib administered in triacetin is reported to be of 3000 mg/kg.[F2971]
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.[A173872]
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.[A173857] The oral bioavailability of glasdegib is reported to be of 55%.[A40310] 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.[A173857] The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.[FDA label]
MOA
Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor.[A40310]; ; 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.[A173860]
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.[FDA 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.[FDA label]; ; The reported oral LD50 in rat of gladegib administered in triacetin is reported to be of 3000 mg/kg.[F2971]
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.[A173857] The oral bioavailability of glasdegib is reported to be of 55%.[A40310]; ; 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.[A173857]; ; The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.[FDA label]
DESCRIPTION
Glasdegib is a potent and orally active inhibitor of the hedgehog signalling pathway, that acts as an antagonist of the class frizzled GPCR, smoothened (SMO) .
(GtoPdb)
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.[A173857]; ; 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.[A173857]; ; 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.[L5080]
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.[L5080]; ; 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.[L4832]
DESCRIPTION
Potent and selective CCR4 antagonist
(Tocris Bioactive Compound Library)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Compound Sets
20
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2017/18
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
MedChem Express Bioactive Compound Library
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
Tocris Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
40
Molecular Weight
374.19
Hydrogen Bond Acceptors
4
Hydrogen Bond Donors
3
Rotatable Bonds
3
Ring Count
4
Aromatic Ring Count
3
cLogP
3.39
TPSA
96.84
Fraction CSP3
0.29
Chiral centers
2.0
Largest ring
6.0
QED
0.65
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Stem cell
GPCR/G protein
Stem Cell/Wnt
Target
Smoothened
SMO
Hedgehog/Smoothened
Primary Target
Smoothened Receptors
MOA
Antagonist
Hedgehog pathway inhibitor
Indication
acute myeloid leukemia (AML)
Source data
