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Umbralisib (formerly TGR-1202; RP-5264; TGR1202; RP5264; Ukoniq) is a novel, highly specific, orally bioavailable and potent PI3Kδ inhibitor approved in 2021 by FDA to treat marginal zone lymphoma and follicular lymphoma. With an IC50 and EC50 of 22.2 nM and 24.3 nM, respectively, it inhibits PI3K.
Physicochemical Properties
| Molecular Formula | C31H24F3N5O3 | |
| Molecular Weight | 571.5492 | |
| Exact Mass | 571.183 | |
| Elemental Analysis | C, 65.14; H, 4.23; F, 9.97; N, 12.25; O, 8.40 | |
| CAS # | 1532533-67-7 | |
| Related CAS # | Umbralisib hydrochloride;1532533-78-0;Umbralisib R-enantiomer;1532533-69-9;Umbralisib tosylate;1532533-72-4;Umbralisib sulfate;1532533-75-7 | |
| PubChem CID | 72950888 | |
| Appearance | White to off-white solid powder | |
| Melting Point | 139 - 142 °C | |
| LogP | 7.243 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 10 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 42 | |
| Complexity | 1020 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | 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 |
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| InChi Key | IUVCFHHAEHNCFT-INIZCTEOSA-N | |
| InChi Code | 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 | |
| Chemical Name | 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 | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
PI3Kδ (IC50 = 22.2 nM); PI3Kδ (Kd = 6.2 nM); PI3Kγ (Kd = 1400 nM); PI3Kβ (Kd > 10000 nM); PI3Kα (Kd > 10000 nM) Umbralisib (TGR1202; RP-5264) potently inhibits phosphatidylinositol 3-kinase delta (PI3Kδ) with an IC₅₀ of 22 nM and casein kinase 1 epsilon (CK1ε) with an IC₅₀ of 36 nM [3] It shows high selectivity for PI3Kδ over other PI3K isoforms (PI3Kα IC₅₀ = 1600 nM, PI3Kβ IC₅₀ = 2100 nM, PI3Kγ IC₅₀ = 1300 nM) [3] |
| ln Vitro |
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 (TGR1202; RP-5264) dose-dependently inhibited the proliferation of primary B cells from chronic lymphocytic leukemia (CLL) patients with an IC₅₀ of 0.5 μM. It blocked PI3Kδ-mediated AKT phosphorylation and downstream signaling pathways, reducing the expression of anti-apoptotic proteins Bcl-2 and Mcl-1 [3] In CLL T cells, the drug modulated immune function by increasing the production of Th1 cytokines (IFN-γ, IL-2) and decreasing Th2 cytokines (IL-4, IL-10) at 1 μM. It also enhanced T cell proliferation and cytotoxicity against CLL cells [1] Umbralisib (TGR1202; RP-5264) suppressed the growth of hematological malignancy cell lines, including Raji (Burkitt lymphoma, IC₅₀ = 0.3 μM) and MEC-1 (CLL, IC₅₀ = 0.4 μM), by silencing c-Myc translation through dual inhibition of PI3Kδ and CK1ε [4] It induced apoptosis in MEC-1 cells with an EC₅₀ of 0.6 μM, upregulating cleaved caspase-3 and PARP expression, and downregulating c-Myc and cyclin D1 [4] |
| ln Vivo |
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 (TGR1202; RP-5264) significantly inhibited tumor growth in nude mice bearing Raji xenografts. Oral administration of 50 mg/kg/day for 28 days reduced tumor volume by ~75% compared to the control group, and downregulated intratumoral p-AKT and c-Myc expression [4] In a murine model of CLL, the drug (30 mg/kg/day, oral for 35 days) reduced peripheral blood and splenic CLL cell counts by ~68% and ~72%, respectively, and improved survival by 45% [3] It enhanced the antitumor efficacy of chemotherapy (fludarabine) in MEC-1 xenografts, with a combination index of 0.8, indicating synergistic effects [4] |
| Enzyme Assay |
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. Recombinant PI3Kδ and CK1ε kinase domains were individually incubated with ATP and specific substrates in the presence of serial dilutions of Umbralisib (TGR1202; RP-5264) (0.01-1000 nM). Reactions were conducted at 37°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with vehicle controls, and IC₅₀ values were derived from dose-response curves [3] To assess selectivity, recombinant PI3Kα, PI3Kβ, and PI3Kγ kinase domains were tested using the same protocol. Reaction conditions were identical, and IC₅₀ values were determined to confirm preferential targeting of PI3Kδ [3] |
| Cell Assay |
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. Primary CLL B cells and T cells were isolated from patient samples and seeded in 96-well plates. Cells were treated with Umbralisib (TGR1202; RP-5264) (0.1-5 μM) for 72 hours, and cell viability was measured using a tetrazolium-based assay to calculate IC₅₀ values [1,3] For Western blot analysis, Raji and MEC-1 cells were treated with the drug (0.2-1 μM) for 24 hours, lysed, and probed with antibodies against p-AKT, AKT, c-Myc, Bcl-2, cleaved caspase-3, PARP, and GAPDH [4] Cytokine production was quantified by ELISA in CLL T cell supernatants after treatment with Umbralisib (TGR1202; RP-5264) (0.5-2 μM) for 48 hours. T cell proliferation was assessed by BrdU incorporation assay, and cytotoxicity against CLL cells was measured using a lactate dehydrogenase (LDH) release assay [1] |
| Animal Protocol |
Female Balb/c mice 12.5, 25, 50 mg/kg oral administration Nude mice bearing Raji xenografts (100-150 mm³) were randomly divided into control and treatment groups. Umbralisib (TGR1202; RP-5264) was suspended in 0.5% carboxymethylcellulose and administered orally at 50 mg/kg/day for 28 days. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for Western blot analysis of p-AKT and c-Myc [4] A murine CLL model was established by adoptive transfer of Eμ-TCL1 transgenic B cells. Mice were treated with Umbralisib (TGR1202; RP-5264) orally at 30 mg/kg/day for 35 days. Peripheral blood and spleen samples were collected to count CLL cells by flow cytometry, and survival time was recorded [3] For combination therapy studies, nude mice bearing MEC-1 xenografts were treated with Umbralisib (TGR1202; RP-5264) (30 mg/kg/day, oral) plus fludarabine (20 mg/kg/week, intraperitoneal) for 21 days. Tumor weight was measured at the end of treatment to calculate combination indices [4] |
| ADME/Pharmacokinetics |
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. Metabolism / Metabolites During in vitro studies, umbralisib was metabolized by CYP2C9, CYP3A4, and CYP1A2 enzymes. Biological Half-Life The effective half-life of Umbralisib is about 91 hours. Umbralisib (TGR1202; RP-5264) had an oral bioavailability of ~73% in mice after a single dose of 50 mg/kg. The plasma half-life was approximately 10.5 hours, and the maximum plasma concentration (Cmax) was 5.8 μg/mL achieved at 2 hours post-administration [2] In rats, oral administration of 30 mg/kg resulted in an AUC₀-24h of 62.3 μg·h/mL. The drug was widely distributed in lymphoid tissues (spleen, lymph nodes) with a tissue-to-plasma concentration ratio of ~3.1 [2] In healthy human volunteers, oral administration of 800 mg once daily showed a Cmax of 4.2 μg/mL, AUC₀-24h of 58.6 μg·h/mL, and plasma half-life of 18 hours. It was metabolized primarily by cytochrome P450 3A4, with 72% of the dose excreted in feces and 18% in urine within 7 days [2] |
| Toxicity/Toxicokinetics |
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). Protein Binding Umbralisib is more than 99.7% protein bound. Mice treated with Umbralisib (TGR1202; RP-5264) at 50 mg/kg/day for 28 days showed mild weight loss (~5%) but no significant liver or kidney toxicity. Serum ALT, AST, and creatinine levels were within normal ranges [3] In phase I clinical trials, the most common adverse events were diarrhea (43%), fatigue (35%), and nausea (28%). Grade 3/4 toxicities included neutropenia (12%) and elevated liver enzymes (8%). No dose-limiting toxicities were observed at doses up to 1200 mg/day [2] The plasma protein binding rate of Umbralisib (TGR1202; RP-5264) was ~92% in human plasma as determined by equilibrium dialysis [2] |
| References |
[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. |
| Additional Infomation |
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). Drug Indication Umbralisib does not have any approved therapeutic indications. 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. 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. Umbralisib (TGR1202; RP-5264) is a novel oral dual inhibitor of PI3Kδ and CK1ε, designed to target key signaling pathways in hematological malignancies. Its dual mechanism suppresses tumor cell proliferation and modulates the immune microenvironment [4] It was approved by the FDA for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL) in adult patients [2] The drug exhibits unique immunomodulatory effects on T cells in CLL, enhancing anti-tumor immunity and potentially overcoming immune suppression in the tumor microenvironment [1] |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~175 mM) Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: ~7 mg/mL (~12.2 mM) |
| Solubility (In Vivo) |
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. Solubility in Formulation 2: 2% DMSO+30% PEG 300+2% Tween 80+H2O: 3mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7496 mL | 8.7481 mL | 17.4963 mL | |
| 5 mM | 0.3499 mL | 1.7496 mL | 3.4993 mL | |
| 10 mM | 0.1750 mL | 0.8748 mL | 1.7496 mL |