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| Targets |
Zandelisib targets phosphatidylinositol 3-kinase delta (PI3Kδ). PI3Kδ is a member of the Class I PI3K family of lipid kinases. It is predominantly expressed in leukocytes and is a key component of the B-cell receptor (BCR) signaling pathway. Activation of the BCR leads to the recruitment and activation of PI3Kδ, which catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP₂) to phosphatidylinositol-3,4,5-trisphosphate (PIP₃). PIP₃ serves as a docking site for downstream signaling molecules, leading to the activation of pathways that promote cell survival, proliferation, and activation. By inhibiting PI3Kδ, zandelisib blocks this signaling cascade, leading to the death of malignant B cells.
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| ln Vitro |
Zandelisib inhibits PI3Ks, with IC50 values for p110α, p110β, p110γ, and p110δ of 4, 976 nM, 605 nM, 817 nM, and 3.5 nM, respectively [1].
In vitro, zandelisib selectively inhibits PI3Kδ with high potency. It has been shown to inhibit the proliferation of B-cell lymphoma cell lines and to induce apoptosis. The compound's activity is typically assessed using cell viability assays, apoptosis assays, and by measuring the phosphorylation of downstream signaling molecules, such as AKT. Zandelisib is also evaluated in combination with other anticancer agents to assess potential synergistic effects. |
| ln Vivo |
In vivo, zandelisib has demonstrated efficacy in mouse models of B-cell lymphoma. Oral administration of the compound led to tumor regression and prolonged survival. The compound's in vivo activity is attributed to its ability to inhibit PI3Kδ and block BCR signaling. Zandelisib is being evaluated in clinical trials for the treatment of various B-cell malignancies.
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| Enzyme Assay |
In vitro enzyme assays for zandelisib involve measuring its inhibition of PI3Kδ activity. The assay is performed using purified PI3Kδ and a substrate, such as PIP₂. The production of PIP₃ is measured using a radioactive or luminescent assay. The IC₅₀ for inhibition is determined from the dose-response curve. The selectivity of the compound for PI3Kδ over other PI3K isoforms (α, β, γ) is also assessed.
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| Cell Assay |
For in vitro cellular assays, the effect of zandelisib on B-cell lymphoma cell lines is typically assessed. Cells are treated with various concentrations of zandelisib, and cell viability is measured using an MTT or resazurin assay. Apoptosis is assessed by flow cytometry using annexin V staining. The phosphorylation of AKT and other downstream signaling molecules is measured by Western blot. These assays provide a measure of the compound's activity in a cellular context.
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| Animal Protocol |
In vivo efficacy of zandelisib is evaluated in xenograft mouse models. Immunodeficient mice are implanted with B-cell lymphoma cells. When tumors reach a certain size, zandelisib is administered orally at various doses. Tumor volume is measured regularly, and final tumor weights are recorded. The compound's ability to inhibit tumor growth is assessed by comparing tumor volumes and weights between treated and control groups.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties for zandelisib indicate that it is orally bioavailable. The compound is absorbed after oral administration and reaches systemic circulation. Its half-life, volume of distribution, and clearance have been characterized in preclinical and clinical studies.
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| Toxicity/Toxicokinetics |
Zandelisib has been evaluated in clinical trials. Common adverse events include diarrhea, nausea, and infections. The compound is generally well-tolerated.
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| References | |
| Additional Infomation |
Zandelisib is an orally bioavailable inhibitor of phosphatidylinositol 3-kinase (PI3K) δ isoform with potential antitumor activity. Oral administration of Zandelisib selectively inhibits the PI3K δ isoform and blocks activation of the PI3K/AKT signaling pathway. This reduces the proliferation of PI3K-δ-overexpressing tumor cells and induces their death. PI3K-δ plays a crucial role in the proliferation and survival of hematologic malignancies. Targeted inhibition of PI3K-δ aims to preserve PI3K signaling in normal non-tumor cells. PI3K is an enzyme frequently overexpressed in cancer cells and plays a vital role in the regulation and survival of tumor cells.
Drug Indications Therapy for mature B-cell tumors Zandelisib is an oral, selective PI3Kδ inhibitor being developed for B-cell malignancies. It is not yet approved for clinical use. |
| Molecular Formula |
C31H38F2N8O
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|---|---|
| Molecular Weight |
576.683232784271
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| Exact Mass |
576.313
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| CAS # |
1401436-95-0
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| PubChem CID |
66571003
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| Appearance |
White to off-white solid powder
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| Boiling Point |
729.2±70.0 °C(Predicted)
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| LogP |
5.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
42
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| Complexity |
855
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1=NC2C=CC=CC=2N1C1N=C(N=C(N=1)NC(C)(C)CC1=CC=CC=C1C1CCN(C)CC1)N1CCOCC1)F
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| InChi Key |
WPFUFWIHMYZXSF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H38F2N8O/c1-31(2,20-22-8-4-5-9-23(22)21-12-14-39(3)15-13-21)38-28-35-29(40-16-18-42-19-17-40)37-30(36-28)41-25-11-7-6-10-24(25)34-27(41)26(32)33/h4-11,21,26H,12-20H2,1-3H3,(H,35,36,37,38)
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| Chemical Name |
4-[2-(difluoromethyl)benzimidazol-1-yl]-N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-6-morpholin-4-yl-1,3,5-triazin-2-amine
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| Synonyms |
Zandelisib; ME401; Zandelisib; 1401436-95-0; PWT143; ACC-524; PW-143; ME-401; ME 401
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~33.33 mg/mL (~57.80 mM )
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.34 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.34 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7341 mL | 8.6703 mL | 17.3406 mL | |
| 5 mM | 0.3468 mL | 1.7341 mL | 3.4681 mL | |
| 10 mM | 0.1734 mL | 0.8670 mL | 1.7341 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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