PI3Kδ (IC50 = 22.2 nM); PI3Kδ (Kd = 6.2 nM); PI3Kγ (Kd = 1400 nM); PI3Kβ (Kd > 10000 nM); PI3Kα (Kd > 10000 nM)

Umbralisib causes a half-maximal inhibition of human whole blood CD19 cell proliferation between 100-300 nM[3].Umbralisib (10 nM-100 μM) inhibits phosphorylated AKT at Ser473 in a concentration-dependent manner in human lymphoma and leukemia cell lines[4].Umbralisib (15-50 μM) is specifically characterized by structural features suitable for targeting CK1 in lymphoma cells, and it potently inhibits the expression of c-Myc in the DLBCL cell line LY7[4].

Umbralisib (150 mg/kg, daily p.o.) significantly shrinks the tumors by day 25 in a subcutaneous xenograft model of T-cell acute lymphoblastic leukemia (T-ALL) in NOD/SCID mice using the MOLT-4 cell line[4].

Umbralisib (TGR-1202) is a novelPI3Kδinhibitor, withIC50andEC50of 22.2 nM and 24.3 nM, respectively; Umbralisib (TGR-1202) is also active againstCK1ε, with anEC50value of 6.0 μM.

Multiple Myeloma resistant (MM-1R) or sensitive (MM-1S) cells are incubated with desired concentrations of RP5264. After 96 hours, a MTT assay is used to measure growth.

Female Balb/c mice
12.5, 25, 50 mg/kg
oral administration

Absorption, Distribution and Excretion
Umbralisib is rapidly absorbed in the GI tract. 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%.
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.
The average apparent central volume of distribution of umbralisib is 312 L.
The average apparent clearance of umbralisib is 15.5 L/h.

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Metabolism / Metabolites
During in vitro studies, umbralisib was metabolized by CYP2C9, CYP3A4, and CYP1A2 enzymes.

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Biological Half-Life
The effective half-life of Umbralisib is about 91 hours.

Hepatotoxicity
In clinical trials of umbralisib in adults with lymphoma, the rates of serum enzyme elevations during therapy ranged from 15% to 35% and were above 5 times the ULN in 5% to 8% and occasionally above 20 times ULN (
Because umbralisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, instances of HBV reactivation were not reported.
Likelihood score: E* (unproven, but suspected rare cause of clinically apparent liver injury).

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Protein Binding
Umbralisib is more than 99.7% protein bound.

[1]. The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020 Jul 14;4(13):3072-3084.

[2]. Umbralisib, a novel PI3Kδ and casein kinase-1ε 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.

[3]. Inhibition of PI3Kδ kinase by a selective, small molecule inhibitor suppresses B-cell proliferation and leukemic cell growth.

[4]. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies. Blood. 2017 Jan 5;129(1):88-99.

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. Follicular lymphoma is also treated with rituximab and other chemotherapeutic agents, but may show similar progression. 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. 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, 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.
Umbralisib is a Kinase Inhibitor. The mechanism of action of umbralisib is as a Kinase Inhibitor.
Umbralisib is an oral kinase inhibitor that is was given accelerated approved for use in adults with relapsed or refractory marginal zone and follicular lymphoma in 2021, but the approval was withdrawn a year later because of data from a trial showing excess mortality with its use. Umbralisib was associated with a modest rate of serum enzyme elevations during therapy but was not reported to cause clinically apparent acute liver with symptoms or jaundice.
Umbralisib is an orally bioavailable, selective inhibitor of the delta isoform of the 110 kDa catalytic subunit of class I phosphoinositide-3 kinases (PI3K) with potential antineoplastic activity. PI3K-delta inhibitor TGR-1202 inhibits PI3K and prevents the activation of the PI3K/AKT kinase signaling pathway. This decreases proliferation and induces cell death in susceptible tumor cells. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in tumor cells and cells of the hematopoietic lineage. The targeted inhibition of PI3K-delta allows for PI3K signaling in normal, non-neoplastic cells. PI3K, an enzyme often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival.
See also: Umbralisib Tosylate (active moiety of).

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Drug Indication
Umbralisib does not have any approved therapeutic indications.

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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. 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. 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.

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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. In addition, Umbralisib inhibits other pathways involved in specific types of lymphoma, including the casein kinase pathway. 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%. 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.

C31H24F3N5O3

571.5492

571.183

C, 65.14; H, 4.23; F, 9.97; N, 12.25; O, 8.40

1532533-67-7

Umbralisib hydrochloride;1532533-78-0;Umbralisib R-enantiomer;1532533-69-9;Umbralisib tosylate;1532533-72-4;Umbralisib sulfate;1532533-75-7

72950888

White to off-white solid powder

139 - 142 °C

7.243

1

10

6

42

1020

1

FC1C([H])=C([H])C2=C(C=1[H])C(C(C1C([H])=C([H])C([H])=C(C=1[H])F)=C([C@]([H])(C([H])([H])[H])N1C3C(=C(N([H])[H])N=C([H])N=3)C(C3C([H])=C([H])C(=C(C=3[H])F)OC([H])(C([H])([H])[H])C([H])([H])[H])=N1)O2)=O

IUVCFHHAEHNCFT-INIZCTEOSA-N

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

2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~175 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: ~7 mg/mL (~12.2 mM)

Solubility in Formulation 1: ≥ 2 mg/mL (3.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 2% DMSO+30% PEG 300+2% Tween 80+H2O: 3mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)