Glasdegib
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Also known as PF-04449913PF-4449913
Summary
Glasdegib (CHEMBL2043437) is an approved small-molecule SMO receptor antagonist (ATC L01XJ03) targeting SMO; indicated across 7 conditions including neoplasm and acute myeloid leukemia.
At a glance
- Status: Approved (max clinical phase 4)
- Modality: Small molecule
- ATC class: L01XJ03
- Targets: 1 (SMO)
- Indications: 7 conditions
- Clinical trials: 25
- Chemistry: 374.4 Da · C21H22N6O
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL2043437 |
| Name | Glasdegib |
| Type | Small molecule |
| Max phase | 4 |
| FDA approved | yes |
| PubChem CID | 25166913 |
| ChEBI | CHEBI:145428 |
| ATC | L01XJ03 |
| Molecular formula | C21H22N6O |
| Molecular weight | 374.4 |
| InChIKey | SFNSLLSYNZWZQG-VQIMIIECSA-N |
SMILES: CN1CC[C@H](C[C@@H]1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N
IUPAC name: 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
ChEBI definition: A member of the class of benzimidazoles that is 1H-benzimidazole which is substituted by a (2R,4S)-4-{[(4-cyanophenyl)carbamoyl]amino}-1-methylpiperidin-2-yl group at position 2. It is a hedgehog signalling pathway inhibitor that acts by binding to Smoothened (SMO) receptors and blocking signal transduction (IC50 = 5 nM). It is used in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients (aged ≥ 75 years), or who have medical conditions that prevent the use of standard chemotherapy.
Pharmacological roles (ChEBI): SMO receptor antagonist, Hedgehog signaling pathway inhibitor, antineoplastic agent.
Also known as: Glasdegib, PF-04449913, PF-4449913, GLASDEGIB
Parent form; salt/anhydrous children: CHEMBL2043440, CHEMBL4297534
Patent coverage: 513 distinct patent families (1,290 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,245 (97%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.
Targets
Targets
Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).
| Gene | Target | Action | pAffinity | Cancer dependency | UniProt |
|---|---|---|---|---|---|
| SMO | SMO | Antagonist | 8.3 | Q99835 |
Broader ChEMBL bioactivity targets: 1 (assay-derived). Sample: Protein smoothened.
Bioactivity
ChEMBL activities: 1 potent at pChembl ≥ 5 of 1 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| P56726 | 8.3 | IC50 | 5 | nM | CHEMBL_ACT_10923808 |
Target pathways
Aggregated over 1 target gene(s): SMO.
Top Reactome pathways
12 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| Signal Transduction | 1 | SMO |
| Organelle biogenesis and maintenance | 1 | SMO |
| Signaling by GPCR | 1 | SMO |
| Class B/2 (Secretin family receptors) | 1 | SMO |
| GPCR ligand binding | 1 | SMO |
| Signaling by Hedgehog | 1 | SMO |
| Hedgehog ‘off’ state | 1 | SMO |
| Cilium Assembly | 1 | SMO |
| Cargo trafficking to the periciliary membrane | 1 | SMO |
| BBSome-mediated cargo-targeting to cilium | 1 | SMO |
| Hedgehog ‘on’ state | 1 | SMO |
| Activation of SMO | 1 | SMO |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| negative regulation of transcription by RNA polymerase II | 1 |
| vasculogenesis | 1 |
| osteoblast differentiation | 1 |
| in utero embryonic development | 1 |
| cell fate specification | 1 |
| neural crest cell migration | 1 |
| negative regulation of protein phosphorylation | 1 |
| heart looping | 1 |
| positive regulation of neuroblast proliferation | 1 |
| positive regulation of mesenchymal cell proliferation | 1 |
| determination of left/right asymmetry in lateral mesoderm | 1 |
| type B pancreatic cell development | 1 |
| protein import into nucleus | 1 |
| apoptotic process | 1 |
| smoothened signaling pathway | 1 |
Indications & clinical
Indications
7 indications (2 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).
| Indication | Trial phase | MONDO | EFO |
|---|---|---|---|
| neoplasm | 4 | MONDO:0005070 | EFO:0000616 |
| acute myeloid leukemia | 3 | MONDO:0018874 | EFO:0000222 |
| soft tissue sarcoma | 3 | MONDO:0018078 | EFO:1001968 |
| myelodysplastic syndrome | 1 | MONDO:0018881 | EFO:0000198 |
| glioblastoma | 1 | MONDO:0018177 | EFO:0000519 |
2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.
Clinical trials
Total trials: 25.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE1 | 9 |
| PHASE2 | 7 |
| PHASE3 | 4 |
| PHASE1/PHASE2 | 4 |
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03416179 | PHASE3 | COMPLETED | A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia |
| NCT03784014 | PHASE3 | COMPLETED | Molecular Profiling of Advanced Soft-tissue Sarcomas |
| NCT04093505 | PHASE3 | TERMINATED | Gemtuzumab Ozogamicin in Induction and Glasdegib in Postremission Therapy in Patients With AML (Acute Myeloid Leukemia) |
| NCT04842604 | PHASE3 | COMPLETED | Continuation Study of B1371019(NCT03416179) and B1371012(NCT02367456) Evaluating Azacitidine With Or Without Glasdegib In Patients With Previously Untreated AML, MDS or CMML |
| NCT04231851 | PHASE2 | ACTIVE_NOT_RECRUITING | CPX-351 and Glasdegib for Newly Diagnosed Acute Myelogenous Leukemia With MDS Related Changes or Therapy-related Acute Myeloid Leukemia |
| NCT01546038 | PHASE2 | COMPLETED | A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome |
| NCT01841333 | PHASE2 | COMPLETED | PF-04449913 For Patients With Acute Myeloid Leukemia at High Risk of Relapse After Donor Stem Cell Transplant |
| NCT01842646 | PHASE2 | COMPLETED | Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS) |
| NCT02226172 | PHASE2 | TERMINATED | Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib |
| NCT03226418 | PHASE2 | COMPLETED | Geriatric Assessment & Genetic Profiling to Personalize Therapy in Older Adults With Acute Myeloid Leukemia |
| NCT03390296 | PHASE1/PHASE2 | COMPLETED | OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia |
| NCT03415867 | PHASE1/PHASE2 | UNKNOWN | Glasdegib in Refractory Patients With Sclerotic Chronic Graft-Versus-Host Disease |
| NCT03466450 | PHASE1/PHASE2 | COMPLETED | Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma |
| NCT04051996 | PHASE2 | TERMINATED | GLAD-AML - Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients With Poor-risk Acute Myeloid Leukemia |
| NCT04111497 | PHASE1/PHASE2 | TERMINATED | Glasdegib for Chronic Graft-Versus-Host Disease |
| NCT00953758 | PHASE1 | COMPLETED | A Study Of PF-04449913 In Select Hematologic Malignancies |
| NCT01286467 | PHASE1 | COMPLETED | A Study Of PF-04449913 Administered Alone In Select Solid Tumors |
| NCT01749085 | PHASE1 | COMPLETED | Study To Determine The Effect Of Food And Strong CYP3A4 Enzyme Inhibitor On PF-04449913 Drug Levels |
| NCT02038777 | PHASE1 | COMPLETED | A Study Of PF-04449913 In Japanese Patients With Select Hematologic Malignancies |
| NCT02110342 | PHASE1 | COMPLETED | A Study To Understand How Radiolabelled PF-04449913 Is Taken Up By The Body, Broken Down And Then Removed From The Body |
| NCT02367456 | PHASE1 | COMPLETED | A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients |
| NCT02430545 | PHASE1 | COMPLETED | Understanding The Effect Of A Strong CYP3A4 Inducer On Glasdegib Pharmacokinetics |
| NCT03130556 | PHASE1 | COMPLETED | A Study Of Glasdegib In Healthy Volunteers To Establish The Bioequivalence Of The Phase 2 Formulation To The ICH Formulation |
| NCT03270878 | PHASE1 | COMPLETED | Glasdegib Absolute Bioavailability Study |
| NCT04230564 | Not specified | WITHDRAWN | Acute Myeloid Leukemia Real World Treatment Patterns |
Clinical evidence (CIViC)
No CIViC predictive evidence (expected for non-precision-medicine drugs).
Pharmacology
Pharmacogenomics
No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.
Related molecules
Related molecules
Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.
10 molecules share ≥1 primary target. Top 10 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| INFIGRATINIB | ChEMBL + PubChem | Phase 4 (approved) | SMO |
| SONIDEGIB | ChEMBL + PubChem | Phase 4 (approved) | SMO |
| VISMODEGIB | ChEMBL + PubChem | Phase 4 (approved) | SMO |
| LINIFANIB | ChEMBL | Phase 3 | SMO |
| PATIDEGIB | ChEMBL | Phase 3 | SMO |
| CEP-32496 | ChEMBL | Phase 2 | SMO |
| FORETINIB | ChEMBL | Phase 2 | SMO |
| TALADEGIB | ChEMBL | Phase 2 | SMO |
| cholecalciferol | PubChem | Approved | SMO |
| Ergocalciferol | PubChem | Approved | SMO |
Related Atlas pages
- Genes: SMO
- Diseases: neoplasm, acute myeloid leukemia, soft tissue sarcoma
- Drugs: Infigratinib, Sonidegib, Vismodegib, Linifanib, Patidegib, cholecalciferol, Ergocalciferol