Find, compare & contact
Umbralisib API Manufacturers & Suppliers

General Description:

Umbralisib, identified by CAS number 1532533-67-7, is a notable compound with significant therapeutic applications. Marginal zone lymphoma is a rare, slowly progressing type of non-Hodgkin lymphoma initially treated with (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it initially offered a promising therapy for patients experiencing relapsing or refractory disease, umbralisib was withdrawn from the market due to safety concerns as the drug was associated with a possible increased risk of death outweighing the benefits.

Indications:

This drug is primarily indicated for: Umbralisib does not have any approved therapeutic indications. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Umbralisib undergoes metabolic processing primarily in: During in vitro studies, umbralisib was metabolized by CYP2C9, CYP3A4, and CYP1A2 enzymes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Umbralisib are crucial for its therapeutic efficacy: 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%. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Umbralisib is an important consideration for its dosing schedule: The effective half-life of Umbralisib is about 91 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Umbralisib exhibits a strong affinity for binding with plasma proteins: Umbralisib is more than 99.7% protein bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Umbralisib from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Umbralisib is distributed throughout the body with a volume of distribution of: The average apparent central volume of distribution of umbralisib is 312 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Umbralisib is a critical factor in determining its safe and effective dosage: The average apparent clearance of umbralisib is 15.5 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Umbralisib exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Umbralisib functions by: 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Umbralisib is categorized under the following therapeutic classes: Antineoplastic 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Umbralisib include:

• Water Solubility: ~100 mg/ml
• Melting Point: 139-142
• logP: 7.24
• pKa: 2.71