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Identification
- Summary
Duvelisib is an inhibitor of phosphatidylinositol 3-kinase delta and gamma used to treat relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
- Brand Names
- Copiktra
- Generic Name
- Duvelisib
- DrugBank Accession Number
- DB11952
- Background
Duvelisib, also known as IPI-145 and INK-1197, is a small-molecule inhibitor of phosphoinositide-3 kinases that was designed initially to prove that simultaneous inhibition of the isoforms delta and gamma can produce a broad adaptative and innate immune cell inhibitory activity. All the work around duvelisib showed that this agent is a potent inhibitor of both forms.1 Duvelisib was developed by Verastem, Inc and FDA approved on September 24, 2018.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Duvelisib (DB11952)
- Weight
- Average: 416.87
Monoisotopic: 416.1152369 - Chemical Formula
- C22H17ClN6O
- Synonyms
- Duvelisib
- External IDs
- INK-1147
- INK-1197
- IPI-145
Pharmacology
- Indication
Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines of systemic therapy.12
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 Refractory chronic lymphocytic leukemia (cll) •••••••••••• ••••• •• ••••• •••••••• ••••••••• ••••••• Treatment of Refractory small lymphocytic lymphoma •••••••••••• ••••• •• ••••• •••••••• ••••••••• ••••••• Treatment of Relapsed chronic lymphocytic leukemia •••••••••••• ••••• •• ••••• •••••••• ••••••••• ••••••• Treatment of Relapsed small lymphocytic lymphoma •••••••••••• ••••• •• ••••• •••••••• ••••••••• ••••••• - Contraindications & Blackbox Warnings
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Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib.4
In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab.7
In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months.7
- Mechanism of action
Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K).2 PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity.3
The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity.4 The specific mechanism of this PI3K inhibitors are further described as follows:
-BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma.4
-The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K.5
-It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells.4
In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response.5
Target Actions Organism APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform inhibitorHumans APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform inhibitorHumans - Absorption
Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9.5 The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile.6
- Volume of distribution
The volume of distribution of duvelisib ranges from 26 to 102 L.6
- Protein binding
The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP.Label
- Metabolism
Duvelesib is mainly metabolized by CYP3A4.Label
- Route of elimination
Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses.5 From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged.Label
- Half-life
The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours.6
- Clearance
Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h.6
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy.Label
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Duvelisib can be increased when it is combined with Abametapir. Abatacept The metabolism of Duvelisib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Duvelisib. Abrocitinib The serum concentration of Duvelisib can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Duvelisib. - Food Interactions
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of duvelisib.
- 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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Copiktra Capsule 15 mg/1 Oral Verastem, Inc. 2018-09-25 Not applicable US 
Copiktra Capsule 15 mg/1 Oral Secura Bio Limited 2018-09-25 Not applicable US Copiktra Capsule 25 mg/1 Oral Verastem, Inc. 2018-09-25 Not applicable US Copiktra Capsule 25 mg Oral Secura Bio Limited 2021-06-01 Not applicable EU 
Copiktra Capsule 15 mg/1 Oral Secura Bio Limited 2018-09-25 Not applicable US
Categories
- ATC Codes
- L01EM04 — Duvelisib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- P-glycoprotein substrates
- Phosphatidylinositol 3-Kinases, antagonists & inhibitors
- Phosphatidylinositol-3-kinase (Pi3K) inhibitors
- Protein Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as isoquinolones and derivatives. These are aromatic polycyclic compounds containing a ketone bearing isoquinoline moiety.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Isoquinolines and derivatives
- Sub Class
- Isoquinolones and derivatives
- Direct Parent
- Isoquinolones and derivatives
- Alternative Parents
- 6-alkylaminopurines / Secondary alkylarylamines / Pyridinones / Aminopyrimidines and derivatives / Aryl chlorides / Benzene and substituted derivatives / Imidolactams / Vinylogous halides / Imidazoles / Heteroaromatic compounds show 7 more
- Substituents
- 6-alkylaminopurine / 6-aminopurine / Amine / Aminopyrimidine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid show 23 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 610V23S0JI
- CAS number
- 1201438-56-3
- InChI Key
- SJVQHLPISAIATJ-ZDUSSCGKSA-N
- InChI
- InChI=1S/C22H17ClN6O/c1-13(28-21-19-20(25-11-24-19)26-12-27-21)17-10-14-6-5-9-16(23)18(14)22(30)29(17)15-7-3-2-4-8-15/h2-13H,1H3,(H2,24,25,26,27,28)/t13-/m0/s1
- IUPAC Name
- 8-chloro-2-phenyl-3-[(1S)-1-[(9H-purin-6-yl)amino]ethyl]-1,2-dihydroisoquinolin-1-one
- SMILES
- C[C@H](NC1=C2N=CNC2=NC=N1)C1=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1
References
- General References
- Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, Pink MM, Proctor JL, Lussier J, Martin CM, Hoyt JG, Tillotson B, Murphy EL, Lim AR, Thomas BD, Macdougall JR, Ren P, Liu Y, Li LS, Jessen KA, Fritz CC, Dunbar JL, Porter JR, Rommel C, Palombella VJ, Changelian PS, Kutok JL: PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74. doi: 10.1016/j.chembiol.2013.09.017. Epub 2013 Nov 7. [Article]
- Authors unspecified: IPI-145 shows promise in CLL patients. Cancer Discov. 2014 Feb;4(2):136. doi: 10.1158/2159-8290.CD-NB2013-177. Epub 2013 Dec 12. [Article]
- Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [Article]
- Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [Article]
- Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [Article]
- Flinn IW, O'Brien S, Kahl B, Patel M, Oki Y, Foss FF, Porcu P, Jones J, Burger JA, Jain N, Kelly VM, Allen K, Douglas M, Sweeney J, Kelly P, Horwitz S: Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic malignancies. Blood. 2018 Feb 22;131(8):877-887. doi: 10.1182/blood-2017-05-786566. Epub 2017 Nov 30. [Article]
- FDA news [Link]
- Canadian Cancer Society [Link]
- Cancer.gov [Link]
- Canadian Cancer Society [Link]
- FDA Approved Drug Products: Copiktra (duvelisib) capsules for oral use [Link]
- FDA Approved Drug Products: COPIKTRA (duvelisib), capsules for oral use (July 2024) [Link]
- External Links
- KEGG Drug
- D10555
- PubChem Compound
- 50905713
- PubChem Substance
- 347828278
- ChemSpider
- 28637766
- BindingDB
- 50193013
- 2058509
- ChEBI
- 131169
- ChEMBL
- CHEMBL3039502
- ZINC
- ZINC000088346058
- Wikipedia
- Duvelisib
- FDA label
- Download (307 KB)
- MSDS
- Download (13.2 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 Not Yet Recruiting Not Available Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) / Diffuse Large B-Cell Lymphoma (DLBCL) / Follicular Lymphoma ( FL) / Marginal Zone Lymphoma (MZL) / Peripheral T-Cell Lymphoma (PTCL) / Richter's Syndrome 1 somestatus stop reason just information to hide Not Available Terminated Not Available Chronic Lymphocytic Leukemia / Follicular Lymphoma ( FL) / Lymphoma / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma 1 somestatus stop reason just information to hide 3 Completed Treatment Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma 2 somestatus stop reason just information to hide 3 Not Yet Recruiting Treatment Lymphoma 1 somestatus stop reason just information to hide 3 Terminated Treatment Follicular Lymphoma ( FL) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 15 MG Capsule Oral 15 mg/1 Capsule Oral 25 MG Capsule Oral 25 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9216982 No 2015-12-22 2029-01-05 US US9840505 No 2017-12-12 2032-01-10 US US8193182 No 2012-06-05 2030-02-13 US USRE46621 No 2017-12-05 2032-05-17 US US11312718 No 2012-01-10 2032-01-10 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >190 ºC 'MSDS' water solubility <1 mg/ml 'MSDS' logP 4.55 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.0195 mg/mL ALOGPS logP 3.91 ALOGPS logP 3.67 Chemaxon logS -4.3 ALOGPS pKa (Strongest Acidic) 9.86 Chemaxon pKa (Strongest Basic) 3.99 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 86.8 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 118.53 m3·mol-1 Chemaxon Polarizability 42.2 Å3 Chemaxon Number of Rings 5 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 splash10-014i-0000900000-18d783c0b2b465dd411a Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00lr-9033600000-44ab4d3339262507f71d Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9105200000-6d8085e81cf542e8ba00 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0100900000-d40f5c612640b596fcd4 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0feo-7139000000-d08e1a1b35272bb03828 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00ks-1956200000-785db42a9690510ffda0 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]- 186.67711 predictedDeepCCS 1.0 (2019) [M+H]+ 189.03511 predictedDeepCCS 1.0 (2019) [M+Na]+ 195.12825 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation, activation, and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. In neutrophils, participates in a phospholipase C-activating N-formyl peptide-activated GPCR (G protein-coupled receptor) signaling pathway downstream of RASGRP4-mediated Ras-activation, to promote neutrophil functional responses (By similarity)
- Specific Function
- 1-phosphatidylinositol-3-kinase activity
- Gene Name
- PIK3CG
- Uniprot ID
- P48736
- Uniprot Name
- Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
- Molecular Weight
- 126452.625 Da
References
- Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [Article]
- Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [Article]
- Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:9235916). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Plays a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Plays important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity
- Specific Function
- 1-phosphatidylinositol-3-kinase activity
- Gene Name
- PIK3CD
- Uniprot ID
- O00329
- Uniprot Name
- Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
- Molecular Weight
- 119478.065 Da
References
- Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [Article]
- Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [Article]
- Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
Drug created at October 20, 2016 21:04 / Updated at October 30, 2024 22:49