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Identification
- Summary
Ingenol mebutate is a topical agent used for the treatment of actinic keratosis.
- Generic Name
- Ingenol mebutate
- DrugBank Accession Number
- DB05013
- Background
Ingenol mebutate was approved by the FDA in January 2012, and it is marketed under the name Picato®. Picato gel is indicated for the topical treatment of actinic keratosis. Before approval, ingenol mebutate was called PEP005 as an investigational drug. PEP005 is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. PEP005 also has potent anti-leukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary AML cells at nanomolar concentrations.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Ingenol mebutate (DB05013)
- Weight
- Average: 430.541
Monoisotopic: 430.235538815 - Chemical Formula
- C25H34O6
- Synonyms
- 3-Angeloylingenol
- 3-Ingenyl angelate
- Ingenol 3-angelate
- Ingenol mebutate
- Ingenol mebutato
- Ingenoli mebutas
- Mébutate d'ingénol
- Mebutato de ingenol
- External IDs
- AGN 204332
- PEP-005
- PEP005
Pharmacology
- Indication
For the topical treatment of actinic keratosis.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Actinic keratosis •••••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
The pharmacodynamics of ingenol mebutate in producing cell death in actinic keratosis is unknown.
- Mechanism of action
The exact mechanism of action of ingenol mebutate in actinic keratosis is unknown. It is presumed to involve primary necrosis then neutrophil-mediated inflammation and antibody-dependent cell death of residual disease cells. Additionally in early studies, PEP005 was shown to be an effective activator of PKC-delta and PKC-delta translocation into nucleus and membranes. PEP005 also downregulates the expression and activity of PKC-alpha. PEP005 induced modulation of PKCs leads to Ras/Raf/MAPK and p38 activation and AKT/PKB inhibition.
Target Actions Organism UProtein kinase C delta type ligandHumans UProtein kinase C alpha type ligandHumans - Absorption
Since ingenol mebutate is a topical treatment, the systemic absorption is less than 0.1 ng/mL.
- Volume of distribution
There is no volume of distribution quantity since ingenol mebutate is a topical treatment.
- Protein binding
There is no plasma protein binding quantity since ingenol mebutate is a topical treatment
- Metabolism
There is no metabolism of Picato since ingenol mebutate is a topical treatment, and ingenol mebutate does not inhibit or induce a majority of the cytochrome P450 (CYP) enzymes.
- Route of elimination
There is no route of elimination since ingenol mebutate is a topical treatment.
- Half-life
There is no half-life quantity since ingenol mebutate is a topical treatment.
- Clearance
There is no clearance quantity since ingenol mebutate is a topical treatment.
- Adverse Effects
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The most common adverse reactions are local skin reactions at the application site, headache, periorbital edema,and nasopharyngitis.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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.No interactions found.
- Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Picato gel ( LEO Pharma)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Picato Gel 150 micrograms/g Cutaneous Leo Laboratories Ltd 2016-09-08 2020-07-06 EU 
Picato Gel 500 ug/1g Topical LEO Pharma Inc. 2012-01-23 2022-04-30 US 
Picato Gel 0.05 % Topical Leo Pharma 2013-03-21 2020-10-14 Canada 
Picato Gel 150 ug/1g Topical LEO Pharma Inc. 2012-01-23 2022-02-28 US Picato Gel 500 micrograms/g Cutaneous Leo Laboratories Ltd 2016-09-08 2020-07-06 EU
Categories
- ATC Codes
- D06BX02 — Ingenol mebutate
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as tigliane and ingenane diterpenoids. These are diterpenoids containing the tigliane or ingenane carbon skeleton. The tigliane skeleton is a tetracyclic ring that consists of the 4/7/6/3 ring junction. It is derived from casbane by 6,10- and 5,14-cyclizations and is a framework of phorbol. The ingenane skeleton is derived by rearrangement of tigliane.
- Kingdom
- Organic compounds
- Super Class
- Lipids and lipid-like molecules
- Class
- Prenol lipids
- Sub Class
- Diterpenoids
- Direct Parent
- Tigliane and ingenane diterpenoids
- Alternative Parents
- Fatty acid esters / Tertiary alcohols / Enoate esters / Secondary alcohols / Ketones / Monocarboxylic acids and derivatives / Primary alcohols / Organic oxides / Hydrocarbon derivatives
- Substituents
- Alcohol / Aliphatic homopolycyclic compound / Alpha,beta-unsaturated carboxylic ester / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Enoate ester / Fatty acid ester / Fatty acyl / Hydrocarbon derivative
- Molecular Framework
- Aliphatic homopolycyclic compounds
- External Descriptors
- carboxylic ester, tetracyclic diterpenoid, cyclic terpene ketone (CHEBI:66913)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 7686S50JAH
- CAS number
- 75567-37-2
- InChI Key
- VDJHFHXMUKFKET-UXMMOKKRSA-N
- InChI
- InChI=1S/C25H34O6/c1-7-12(2)22(29)31-21-13(3)10-24-14(4)8-17-18(23(17,5)6)16(20(24)28)9-15(11-26)19(27)25(21,24)30/h7,9-10,14,16-19,21,26-27,30H,8,11H2,1-6H3/b12-7-/t14-,16-,17-,18+,19-,21+,24+,25+/m1/s1
- IUPAC Name
- (1S,4S,5S,6R,9R,10R,12R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxotetracyclo[7.5.1.0^{1,5}.0^{10,12}]pentadeca-2,7-dien-4-yl (2Z)-2-methylbut-2-enoate
- SMILES
- [H][C@@]12C[C@@H](C)[C@]34C=C(C)[C@H](OC(=O)C(\C)=C/C)[C@@]3(O)[C@H](O)C(CO)=C[C@@]([H])(C4=O)[C@]1([H])C2(C)C
References
- Synthesis Reference
Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine D, Johns J, Scott TM, Sutherland KP, Gardner JM, Le TT, Lenarczyk A, Aylward JH, Parsons PG: Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004 Apr 15;64(8):2833-9.
- General References
- Not Available
- External Links
- KEGG Drug
- D09393
- PubChem Compound
- 6918670
- PubChem Substance
- 175426930
- ChemSpider
- 28533061
- 1242806
- ChEBI
- 66913
- ChEMBL
- CHEMBL1863513
- ZINC
- ZINC000056898854
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ingenol_mebutate
- FDA label
- Download (276 KB)
- MSDS
- Download (24.9 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Actinic Keratosis (AK) 4 somestatus stop reason just information to hide 4 Completed Treatment Actinic Keratosis (AK) 6 somestatus stop reason just information to hide 4 Unknown Status Treatment Actinic Keratosis (AK) 1 somestatus stop reason just information to hide 3 Completed Treatment Actinic Keratosis (AK) 13 somestatus stop reason just information to hide 3 Terminated Treatment Actinic Keratosis (AK) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Gel Cutaneous 150 MICROGRAMMI/G Gel Cutaneous 150 micrograms/g Gel Cutaneous 500 MICROGRAMMI/G Gel Cutaneous 500 micrograms/g Gel Topical 0.015 % Gel Topical 0.05 % Gel Topical 150 ug/1g Gel Topical 500 ug/1g - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region CA2301082 No 2009-02-03 2018-08-19 Canada US7410656 No 2008-08-12 2018-08-19 US US8536163 No 2013-09-17 2026-12-18 US US8716271 No 2014-05-06 2026-12-18 US US8735375 No 2014-05-27 2026-12-18 US US6432452 No 2002-08-13 2018-08-19 US US6787161 No 2004-09-07 2018-08-19 US US6844013 No 2005-01-18 2018-12-13 US US8278292 No 2012-10-02 2027-07-06 US US8377919 No 2013-02-19 2026-12-18 US US8372828 No 2013-02-12 2026-12-18 US US8372827 No 2013-02-12 2026-12-18 US US9789078 No 2017-10-17 2033-05-15 US US9820959 No 2017-11-21 2026-12-18 US US9833429 No 2017-12-05 2026-12-18 US US9833428 No 2017-12-05 2026-12-18 US US9861603 No 2018-01-09 2026-12-18 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.279 mg/mL ALOGPS logP 2.49 ALOGPS logP 2.51 Chemaxon logS -3.2 ALOGPS pKa (Strongest Acidic) 12.13 Chemaxon pKa (Strongest Basic) -2.8 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 104.06 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 117.86 m3·mol-1 Chemaxon Polarizability 47.14 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
Property Value Probability Human Intestinal Absorption + 0.8185 Blood Brain Barrier + 0.5912 Caco-2 permeable - 0.7076 P-glycoprotein substrate Substrate 0.7633 P-glycoprotein inhibitor I Non-inhibitor 0.7201 P-glycoprotein inhibitor II Non-inhibitor 0.8873 Renal organic cation transporter Non-inhibitor 0.9158 CYP450 2C9 substrate Non-substrate 0.8455 CYP450 2D6 substrate Non-substrate 0.8671 CYP450 3A4 substrate Substrate 0.6695 CYP450 1A2 substrate Non-inhibitor 0.6961 CYP450 2C9 inhibitor Non-inhibitor 0.5257 CYP450 2D6 inhibitor Non-inhibitor 0.9137 CYP450 2C19 inhibitor Non-inhibitor 0.817 CYP450 3A4 inhibitor Non-inhibitor 0.8095 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8368 Ames test AMES toxic 0.5474 Carcinogenicity Non-carcinogens 0.9194 Biodegradation Not ready biodegradable 0.7966 Rat acute toxicity 2.7836 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9974 hERG inhibition (predictor II) Non-inhibitor 0.844
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-01q9-0005900000-cfe0403c6e1a4e8a38c8 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-ef55b0cd5e220e268bfb Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-01q9-0019100000-b309b9888fd9b49be136 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-9004200000-cfb7a8c918c2eb627e80 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0pb9-9011000000-45ad5d306b4725680784 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00ke-9102000000-5309597a6c25cab15e88 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Ligand
- General Function
- Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses (PubMed:21406692, PubMed:21810427). Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction (By similarity). Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis (PubMed:21406692, PubMed:21810427). In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53 (PubMed:21406692, PubMed:21810427). In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53 (PubMed:21406692, PubMed:21810427). In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation (By similarity). Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1 (PubMed:15774464). Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Involved in antifungal immunity by mediating phosphorylation and activation of CARD9 downstream of C-type lectin receptors activation, promoting interaction between CARD9 and BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways (By similarity). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways (PubMed:19801500). May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA (PubMed:11748588). In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation (PubMed:16940418). Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release (PubMed:19587372). Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin (PubMed:11877440). The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). Phosphorylates ELAVL1 in response to angiotensin-2 treatment (PubMed:18285462). Phosphorylates mitochondrial phospholipid scramblase 3 (PLSCR3), resulting in increased cardiolipin expression on the mitochondrial outer membrane which facilitates apoptosis (PubMed:12649167). Phosphorylates SMPD1 which induces SMPD1 secretion (PubMed:17303575)
- Specific Function
- Atp binding
- Gene Name
- PRKCD
- Uniprot ID
- Q05655
- Uniprot Name
- Protein kinase C delta type
- Molecular Weight
- 77504.445 Da
References
- Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM: Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004 May 1;64(9):3243-55. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Ligand
- General Function
- Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. During chemokine-induced CD4(+) T cell migration, phosphorylates CDC42-guanine exchange factor DOCK8 resulting in its dissociation from LRCH1 and the activation of GTPase CDC42 (PubMed:28028151). Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF-kappa-B-induced genes, through IL1A-dependent induction of NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. Phosphorylates SOCS2 at 'Ser-52' facilitating its ubiquitination and proteasomal degradation (By similarity). Phosphorylates KLHL3 in response to angiotensin II signaling, decreasing the interaction between KLHL3 and WNK4 (PubMed:25313067)
- Specific Function
- Atp binding
- Gene Name
- PRKCA
- Uniprot ID
- P17252
- Uniprot Name
- Protein kinase C alpha type
- Molecular Weight
- 76749.445 Da
References
- Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM: Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004 May 1;64(9):3243-55. [Article]
Drug created at October 21, 2007 22:23 / Updated at September 15, 2024 01:12