NAV

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it initially offered a promising therapy for patients experiencing relapsing or refractory disease,1 umbralisib was withdrawn from the market due to safety concerns as the drug was associated with a possible increased risk of death outweighing the benefits.10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Approved, Investigational, Withdrawn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
3D
Similar Structures
Weight
Average: 571.56
Monoisotopic: 571.183124142
Chemical Formula
C31H24F3N5O3
Synonyms
  • Umbralisib
External IDs
  • RP-5264
  • TGR 1202
  • TGR-1202
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Pharmacology

Indication

Umbralisib does not have any approved therapeutic indications.

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Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
ACasein kinase I isoform epsilon
inhibitor
Humans
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
inhibitor
Humans
UTyrosine-protein kinase ABL1
inhibitor
Humans
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.
DrugInteraction
Integrate drug-drug
interactions in your software
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Umbralisib.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Umbralisib.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Umbralisib.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Umbralisib is combined with Ambroxol.
ApixabanThe 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

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Product Ingredients
IngredientUNIICASInChI Key
Umbralisib tosylateFU8XW5V3FS1532533-72-4KYJWUPZPSXZEPG-NTISSMGPSA-N
International/Other Brands
UKONIQ (Rhizen Pharmaceuticals AG)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
UkoniqTablet, film coated260.2 mg/1OralTg Therapeutics, Inc.2021-02-052023-07-31US flag

Categories

ATC Codes
L01EX25 — Umbralisib
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. FDA: FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma [Link]
  7. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
  8. Selleck MSDS: Umbralisib [Link]
  9. HMDB MSDS: Umbralisib [Link]
  10. FDA Drug Safety and Availability: FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns [Link]
Human Metabolome Database
HMDB0304848
ChemSpider
34979945
BindingDB
184556
RxNav
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);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentChronic Lymphocytic Leukemia1
2Active Not RecruitingTreatmentChronic Lymphocytic Leukemia / Chronic Lymphocytic Leukemia (CLL) - Refractory / Relapsed Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma1
2Active Not RecruitingTreatmentFollicular 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
2Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1
2CompletedTreatmentChronic Lymphocytic Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral260.2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10072013No2018-09-112033-07-02US flag
US9969740No2018-05-152035-05-26US flag
US10570142No2020-02-252033-07-02US flag
US10414773No2019-09-172035-05-26US flag
US9669033No2017-06-062033-07-02US flag
US9150579No2015-10-062033-07-02US flag
US10947244No2021-03-162035-05-26US flag
US10981919No2021-04-202033-07-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)139-142https://www.chemsrc.com/en/cas/1532533-67-7_329089.html
water solubility~100 mg/mlhttps://hmdb.ca/system/metabolites/msds/000/001/063/original/S-Adenosylmethionine_MSDS.pdf?1368651702
logP7.24https://www.chemsrc.com/en/cas/1532533-67-7_329089.html
pKa2.71https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213176s000lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00168 mg/mLALOGPS
logP5.2ALOGPS
logP6.13Chemaxon
logS-5.5ALOGPS
pKa (Strongest Acidic)19.68Chemaxon
pKa (Strongest Basic)4.01Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area105.15 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity163.22 m3·mol-1Chemaxon
Polarizability56.6 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0001090000-18bd3bd6fdd152786498
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gia-0070290000-7d8982d0a7377ae71816
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0230-0000090000-64a250df226ed941634a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01b9-7050090000-c62eaeeeb07887a22d0f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fkl-0071090000-db276ae50bf3ca4a72c1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0ae9-0190450000-43a2cc2f33a3b0c1c5c0
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Casein kinase I isoform epsilon
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
  1. 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]
  2. 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]
  3. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Details2. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
Details3. Tyrosine-protein kinase ABL1
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
  1. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]

Enzymes

Details1. Cytochrome P450 2C9
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
  1. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Details2. Cytochrome P450 1A2
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
  1. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Details3. Cytochrome P450 3A4
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
  1. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]
Details4. Tyrosine-protein kinase ABL1
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
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use [Link]

Transporters

Details1. P-glycoprotein 1
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
  1. 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