Umbralisib
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Identification
- Summary
Umbralisib is a kinase inhibitor used to treat rare forms of refractory lymphoma.
- Generic Name
- Umbralisib
- DrugBank Accession Number
- DB14989
- Background
Marginal zone lymphoma is a rare, slowly progressing type of non-Hodgkin lymphoma initially treated with rituximab (an anti-CD20 drug), either alone or in combination with chemotherapy. Unfortunately, many patients experience a relapse or develop resistance to these drugs. Treatment options then become limited, and alternate treatments for the lymphoma are required to control disease progression.1 Follicular lymphoma is also treated with rituximab and other chemotherapeutic agents, but may show similar progression.5
On February 5, 2021, the Food and Drug Administration granted accelerated approval to umbralisib, a kinase inhibitor for PI3K-delta and casein kinase CK1-epsilon, based on promising results from clinical trials. It was marketed as Ukoniq by TG Therapeutics and has been approved for the treatment of relapsing and refractory marginal cell lymphoma and follicular lymphoma in adults.6 Umbralisib inhibits casein kinase, a primary regulator of protein translation, kinase-1ε, distinguishing it from other lymphoma treatments. While it initially offered a promising therapy for patients experiencing relapsing or refractory disease,1 umbralisib was withdrawn from the market due to safety concerns as the drug was associated with a possible increased risk of death outweighing the benefits.10
- Type
- Small Molecule
- Groups
- Approved, Investigational, Withdrawn
- Structure
- Weight
- Average: 571.56
Monoisotopic: 571.183124142 - Chemical Formula
- C31H24F3N5O3
- Synonyms
- Umbralisib
- External IDs
- RP-5264
- TGR 1202
- TGR-1202
Pharmacology
- Indication
Umbralisib does not have any approved therapeutic indications.
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- Pharmacodynamics
Umbralisib acts against against marginal zone lymphoma by interrupting the PI3K pathway; this is an essential pathway for B-cell receptor signaling responsible for the progression of lymphoma.2,3,4 In addition, Umbralisib inhibits other pathways involved in specific types of lymphoma, including the casein kinase pathway.7 An overall response rate of 55% was recorded during clinical trials and the rate of 1-year progression free survival from marginal zone lymphoma was 71%.2
A relationship between higher umbralisib steady state exposures and higher incidence of adverse reactions, including diarrhea and elevated AST/ALT was observed during clinical studies. The effect of this drug on QT interval has not been fully characterized.7
- Mechanism of action
The PI3K pathway is a deregulated in malignancies, leading to the overexpression of p110 isoforms (p110α, p110β, p110δ, p110γ) that induces malignant transformation in cells.4 Umbralisib inhibits several protein kinases, including PI3Kδ and casein kinase CK1ε. PI3Kδ is expressed in both healthy cells and malignant B-cells. CK1ε is believed to be involved in the pathogenesis of malignant cells, including lymphomas. This results in reduced progression of relapsed or refractory lymphoma.1,7 In biochemical assays, umbralisib inhibited a mutated form of ABL1. In vitro, umbralisib inhibits malignant cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration.1,7
Target Actions Organism ACasein kinase I isoform epsilon inhibitorHumans APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform inhibitorHumans UTyrosine-protein kinase ABL1 inhibitorHumans - Absorption
Umbralisib is rapidly absorbed in the GI tract.1 The Tmax of umbralisib is about 4 hours. After consumption of a high-fat, high calorie meal with umbralisib, the AUC increased by 61% and the Cmax increased by 115%.7
- Volume of distribution
The average apparent central volume of distribution of umbralisib is 312 L.7
- Protein binding
Umbralisib is more than 99.7% protein bound.7
- Metabolism
During in vitro studies, umbralisib was metabolized by CYP2C9, CYP3A4, and CYP1A2 enzymes.7
- Route of elimination
During pharmacokinetic studies, about 81% of the umbralisib dose was recovered in feces (17% unchanged). Approximately 3% was detected in the urine (0.02% unchanged) after a radiolabeled dose of 800 mg in healthy volunteers.7
- Half-life
The effective half-life of Umbralisib is about 91 hours.7
- Clearance
The average apparent clearance of umbralisib is 15.5 L/h.7
- 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
The oral LD50 of umbralisib in rats is 3320 mg/kg.9 Overdose information is not readily available on prescribing information 7 or the literature. In any overdose, supportive and symptomatic treatment should be provided as required.
- 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 softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Umbralisib. Afatinib The serum concentration of Afatinib can be increased when it is combined with Umbralisib. Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with Umbralisib. Ambroxol The risk or severity of methemoglobinemia can be increased when Umbralisib is combined with Ambroxol. Apixaban The serum concentration of Apixaban can be increased when it is combined with Umbralisib. - Food Interactions
- Take with food. Food increases the bioavailability and concentration of umbralisib.
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.
- Product Ingredients
Ingredient UNII CAS InChI Key Umbralisib tosylate FU8XW5V3FS 1532533-72-4 KYJWUPZPSXZEPG-NTISSMGPSA-N - International/Other Brands
- UKONIQ (Rhizen Pharmaceuticals AG)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ukoniq Tablet, film coated 260.2 mg/1 Oral Tg Therapeutics, Inc. 2021-02-05 2023-07-31 US
Categories
- ATC Codes
- L01EX25 — Umbralisib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2C9 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 inhibitors
- Protein Kinase Inhibitors
- Classification
- Not classified
- Affected organisms
- Rat
Chemical Identifiers
- UNII
- 38073MQB2A
- CAS number
- 1532533-67-7
- InChI Key
- IUVCFHHAEHNCFT-INIZCTEOSA-N
- InChI
- InChI=1S/C31H24F3N5O3/c1-15(2)41-24-9-7-18(12-22(24)34)27-26-30(35)36-14-37-31(26)39(38-27)16(3)29-25(17-5-4-6-19(32)11-17)28(40)21-13-20(33)8-10-23(21)42-29/h4-16H,1-3H3,(H2,35,36,37)/t16-/m0/s1
- IUPAC Name
- 2-[(1S)-1-{4-amino-3-[3-fluoro-4-(propan-2-yloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl]-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
- SMILES
- CC(C)OC1=C(F)C=C(C=C1)C1=NN([C@@H](C)C2=C(C3=CC=CC(F)=C3)C(=O)C3=CC(F)=CC=C3O2)C2=C1C(N)=NC=N2
References
- General References
- Burris HA 3rd, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA: Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018 Apr;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2. Epub 2018 Feb 20. [Article]
- Authors unspecified: Umbralisib: Treatment for a Rare Lymphoma? Cancer Discov. 2019 Jun;9(6):OF5. doi: 10.1158/2159-8290.CD-NB2019-045. Epub 2019 Apr 1. [Article]
- Lunning M, Vose J, Nastoupil L, Fowler N, Burger JA, Wierda WG, Schreeder MT, Siddiqi T, Flowers CR, Cohen JB, Sportelli P, Miskin HP, Weiss MS, O'Brien S: Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019 Nov 21;134(21):1811-1820. doi: 10.1182/blood.2019002118. [Article]
- Curran E, Smith SM: Phosphoinositide 3-kinase inhibitors in lymphoma. Curr Opin Oncol. 2014 Sep;26(5):469-75. doi: 10.1097/CCO.0000000000000113. [Article]
- Freedman A, Jacobsen E: Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020 Mar;95(3):316-327. doi: 10.1002/ajh.25696. Epub 2019 Dec 22. [Article]
- FDA: FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma [Link]
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- Selleck MSDS: Umbralisib [Link]
- HMDB MSDS: Umbralisib [Link]
- FDA Drug Safety and Availability: FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns [Link]
- External Links
- Human Metabolome Database
- HMDB0304848
- ChemSpider
- 34979945
- BindingDB
- 184556
- 2478439
- ChEMBL
- CHEMBL3948730
- ZINC
- ZINC000141831516
- Wikipedia
- Umbralisib
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 data3 Terminated Treatment Chronic Lymphocytic Leukemia 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Chronic Lymphocytic Leukemia / Refractory Chronic Lymphocytic Leukemia (CLL) / Relapsed Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Follicular Lymphoma Grade IIIa / Grade 1 Follicular Lymphoma / Grade 2 Follicular Lymphoma / Recurrent Follicular Lymphoma / Refractory Follicular Lymphoma 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Mantle Cell Lymphoma (MCL) 1 somestatus stop reason just information to hide 2 Completed Treatment Follicular Lymphoma ( FL) / Marginal Zone Lymphoma (MZL) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 260.2 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10072013 No 2018-09-11 2033-07-02 US US9969740 No 2018-05-15 2035-05-26 US US10570142 No 2020-02-25 2033-07-02 US US10414773 No 2019-09-17 2035-05-26 US US9669033 No 2017-06-06 2033-07-02 US US9150579 No 2015-10-06 2033-07-02 US US10947244 No 2021-03-16 2035-05-26 US US10981919 No 2021-04-20 2033-07-02 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 139-142 https://www.chemsrc.com/en/cas/1532533-67-7_329089.html water solubility ~100 mg/ml https://hmdb.ca/system/metabolites/msds/000/001/063/original/S-Adenosylmethionine_MSDS.pdf?1368651702 logP 7.24 https://www.chemsrc.com/en/cas/1532533-67-7_329089.html pKa 2.71 https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213176s000lbl.pdf - Predicted Properties
Property Value Source Water Solubility 0.00168 mg/mL ALOGPS logP 5.2 ALOGPS logP 6.13 Chemaxon logS -5.5 ALOGPS pKa (Strongest Acidic) 19.68 Chemaxon pKa (Strongest Basic) 4.01 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 105.15 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 163.22 m3·mol-1 Chemaxon Polarizability 56.6 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates (Probable). Participates in Wnt signaling (PubMed:12556519, PubMed:23413191). Phosphorylates DVL1 (PubMed:12556519). Phosphorylates DVL2 (PubMed:23413191). Phosphorylates NEDD9/HEF1 (By similarity). Central component of the circadian clock (PubMed:16790549). In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation (PubMed:15917222, PubMed:16790549). Controls PER1 and PER2 nuclear transport and degradation (By similarity). Inhibits cytokine-induced granuloytic differentiation (PubMed:15070676)
- Specific Function
- ATP binding
- Gene Name
- CSNK1E
- Uniprot ID
- P49674
- Uniprot Name
- Casein kinase I isoform epsilon
- Molecular Weight
- 47314.665 Da
References
- Maharaj K, Powers JJ, Achille A, Mediavilla-Varela M, Gamal W, Burger KL, Fonseca R, Jiang K, Miskin HP, Maryanski D, Monastyrskyi A, Duckett DR, Roush WR, Cleveland JL, Sahakian E, Pinilla-Ibarz J: The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020 Jul 14;4(13):3072-3084. doi: 10.1182/bloodadvances.2020001800. [Article]
- Burris HA 3rd, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA: Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018 Apr;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2. Epub 2018 Feb 20. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- 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
- Burris HA 3rd, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA: Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018 Apr;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2. Epub 2018 Feb 20. [Article]
- Authors unspecified: Umbralisib: Treatment for a Rare Lymphoma? Cancer Discov. 2019 Jun;9(6):OF5. doi: 10.1158/2159-8290.CD-NB2019-045. Epub 2019 Apr 1. [Article]
- Lunning M, Vose J, Nastoupil L, Fowler N, Burger JA, Wierda WG, Schreeder MT, Siddiqi T, Flowers CR, Cohen JB, Sportelli P, Miskin HP, Weiss MS, O'Brien S: Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019 Nov 21;134(21):1811-1820. doi: 10.1182/blood.2019002118. [Article]
- Maharaj K, Powers JJ, Achille A, Mediavilla-Varela M, Gamal W, Burger KL, Fonseca R, Jiang K, Miskin HP, Maryanski D, Monastyrskyi A, Duckett DR, Roush WR, Cleveland JL, Sahakian E, Pinilla-Ibarz J: The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020 Jul 14;4(13):3072-3084. doi: 10.1182/bloodadvances.2020001800. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Supported by in vitro data only.
- General Function
- Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9 (PubMed:22810897). Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (PubMed:28428613). ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21-dependent manner (By similarity). Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (By similarity)
- Specific Function
- actin filament binding
- Gene Name
- ABL1
- Uniprot ID
- P00519
- Uniprot Name
- Tyrosine-protein kinase ABL1
- Molecular Weight
- 122871.435 Da
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). 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) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Drug created at May 20, 2019 14:39 / Updated at April 10, 2024 17:34