Umbralisib
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it initially offered a promising therapy for patients experiencing relapsing or refractory disease,1 umbralisib was withdrawn from the market due to safety concerns as the drug was associated with a possible increased risk of death outweighing the benefits.10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- Approved, Investigational, Withdrawn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
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- 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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Completed Treatment Chronic Lymphocytic Leukemia 1 2 Active Not Recruiting Treatment Chronic Lymphocytic Leukemia / Chronic Lymphocytic Leukemia (CLL) - Refractory / Relapsed Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma 1 2 Active Not Recruiting Treatment Follicular Lymphoma ( FL) / Follicular Lymphoma Grade IIIa / Grade 1 Follicular Lymphoma / Grade 2 Follicular Lymphoma / Lymphoma / Marginal Zone B-Cell Lymphoma / Marginal Zone Lymphoma (MZL) 1 2 Active Not Recruiting Treatment Mantle Cell Lymphoma (MCL) 1 2 Completed Treatment Chronic Lymphocytic Leukemia 1
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
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein serine/threonine kinase activity
- Specific Function
- Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Can phosphorylate a large number of proteins. Participates in Wnt signal...
- 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]
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Phosphatidylinositol-4,5-bisphosphate 3-kinase activity
- Specific Function
- Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by rec...
- 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]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Supported by in vitro data only.
- General Function
- Syntaxin binding
- Specific 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 a...
- 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
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- 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
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- 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]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Supported by in vitro data only.
- General Function
- Syntaxin binding
- Specific 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 a...
- Gene Name
- ABL1
- Uniprot ID
- P00519
- Uniprot Name
- Tyrosine-protein kinase ABL1
- Molecular Weight
- 122871.435 Da
References
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- 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 December 01, 2022 11:29