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| Targets |
IC50: 1 nM (PI3Kδ, 1 mM ATP)[1]
Parsaclisib targets phosphoinositide 3-kinase delta (PI3Kδ), a Class I PI3K isoform that is preferentially expressed in hematopoietic cells and plays a critical role in B-cell receptor signaling, proliferation, and survival. The compound has an IC50 of 1 nM for PI3Kδ and shows approximately 20,000-fold selectivity for PI3Kδ over PI3Kα, PI3Kβ, and PI3Kγ. |
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| ln Vitro |
MCL and DLBCL cell lines are inhibited from proliferating by parsaclisib (0.1-3000 nM; 4 d)[2]. In the Ramos Burkitt's lymphoma cell line, parsaclisib (0.1-1000 nM; 2 h) suppresses anti-IgM-induced pAKT (Ser473) with an IC50 of 1 nM[2]. With IC50s ranging from 0.2 to 1.7 nM, parsaclisib reduces the proliferation of primary B cells in humans, dogs, rats, and mice following activation of these receptors[2].
In vitro, Parsaclisib potently inhibits PI3Kδ with an IC50 of 1 nM at 1 mM ATP. It is selective for PI3Kδ over PI3Kα, PI3Kβ, and PI3Kγ (IC50s >10,000 nM for all), as well as a panel of 57 other kinases. Parsaclisib inhibits the proliferation of primary human B cells with an IC50 of 0.2 nM and inhibits cytokine production in memory T cells with IC50s of 0.2-1.5 nM. |
| ln Vivo |
In BALB/c mice harboring A20 murine lymphoma cells, parsaclisib (10 mg/kg; administered orally twice daily for 7–19 days) suppresses tumor formation [2]. Pfeiffer xenograft tumors grow more slowly when parsaclisib (0.1–10 mg/kg; orally twice daily) is administered. This effect is dose-dependent. It's easy to tolerate parsaclisib [2]. pAKT (Ser473) is inhibited by parsaclisib (0.5–1 mg/kg; single oral dose) in the Pfeiffer subcutaneous mouse xenograft model [2].
In vivo, Parsaclisib synergizes with PIM protein kinase inhibition to cause tumor regression in a model of diffuse large B-cell lymphoma (DLBCL). The compound is orally active and has shown efficacy in preclinical models of B-cell malignancies. It has been evaluated in clinical trials for relapsed or refractory B-cell malignancies. |
| Enzyme Assay |
Specific cell-free enzyme/receptor binding assay protocols for Parsaclisib involve PI3K kinase activity assays using purified recombinant PI3K isoforms. IC50 values are determined by measuring the compound's inhibition of PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ activity using radiolabeled ATP or luminescent kinase assays. Selectivity is confirmed by screening against a panel of 57 additional kinases.
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| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: Jeko-1, Mino, JVM2, Rec-1, Pfeiffer, SU-DHL-5, SU-DHL-6, WSU-NHL, SU-DHL-4, SU-DHL-8, and WILL-2 cells Tested Concentrations: 0.1-3000 nM Incubation Duration: 4 days Experimental Results: Resulted in a maximal inhibition of 70-90%, with IC50s of ≤10 nM in the four MCL cell lines. Pfeiffer, SU-DHL-5, SU-DHL-6, and WSU-NHL were highly sensitive, with IC50s from 2 to 8 nM. In vitro cell-based assays for Parsaclisib use primary human B cells and memory T cells. Cells are treated with Parsaclisib, and proliferation is measured by [³H]-thymidine incorporation or CFSE dilution. Cytokine production is measured by ELISA or multiplex assays. The compound's effects on PI3Kδ signaling are assessed by measuring phosphorylation of downstream targets such as AKT. |
| Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse (5-9 weeks) were inoculated with A20 cells [2]
Doses: 10 mg/kg Route of Administration: po (oral gavage), twice a day for 7-19 days Experimental Results: Produced significant Tumor Growth Inhibition (TGI). Reduces the percentage of Tregs (CD4+CD25+FOXP3+) in tumors and spleen. Increased ratio of CD4+ and CD8+ T cells to Tregs in spleen and tumors. Reduces the number of CD4+CD44high and CD8+CD44high T cells in the spleen and tumors. In vivo animal studies for Parsaclisib have been conducted in mouse models of DLBCL. Tumor-bearing mice are treated with Parsaclisib alone or in combination with PIM inhibitors, and tumor growth inhibition is monitored. The compound's effects on B-cell proliferation and survival are assessed. Pharmacodynamic markers such as AKT phosphorylation are measured in tumor tissues. |
| ADME/Pharmacokinetics |
Parsaclisib has a molecular formula of C20H22ClFN6O2 and a molecular weight of 432.88 g/mol. The compound is orally active and shows favorable oral bioavailability. It is soluble in DMSO. Storage: powder at -20°C for 3 years or 4°C for 2 years; in solvent at -80°C for 6 months or -20°C for 1 month.
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| Toxicity/Toxicokinetics |
Specific toxicological data for Parsaclisib are not extensively detailed in the available literature. The compound has been evaluated in clinical trials for relapsed or refractory B-cell malignancies, indicating that safety assessments have been conducted. As a PI3Kδ inhibitor, potential toxicities may include immunosuppression and gastrointestinal effects.
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| References |
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| Additional Infomation |
Parsaclisib is being investigated in the clinical trial NCT03126019 (an open-label study of parsaclisib for the treatment of relapsed or refractory follicular lymphoma (CITADEL-203)). Parsaclisib is an inhibitor of the phosphatidylinositol-3 kinase (PI3K) δ isoform with potential antitumor activity. Parsaclisib inhibits the PI3K δ isoform, thereby preventing the activation of the PI3K/AKT signaling pathway. This both reduces the proliferation of PI3K δ-overexpressing tumor cells and induces their death. Unlike other PI3K isoforms, PI3K δ is primarily expressed in hematopoietic system diseases and cell lineages. 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 crucial role in the regulation and survival of tumor cells.
Drug Indications Therapeutic use of parsaclisib for the treatment of mature B-cell malignancies Parsaclisib (INCB050465) (CAS 1426698-88-5) is a potent, selective, orally active PI3Kδ inhibitor with an IC50 of 1 nM. It shows approximately 20,000-fold selectivity over PI3Kα, PI3Kβ, PI3Kγ, and 57 other kinases. The compound inhibits primary human B cell proliferation (IC50 = 0.2 nM) and synergizes with PIM inhibition in DLBCL models. No approved indication data are available. |
| Molecular Formula |
C20H22CLFN6O2
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|---|---|
| Molecular Weight |
432.879086017609
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| Exact Mass |
432.147
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| CAS # |
1426698-88-5
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| Related CAS # |
Parsaclisib hydrochloride;1995889-48-9
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| PubChem CID |
86677874
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
650.9±55.0 °C at 760 mmHg
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| Flash Point |
347.5±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.704
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| LogP |
1.36
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
632
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CCOC1=C(C(=C(C=C1[C@H](C)N2C3=NC=NC(=C3C(=N2)C)N)Cl)F)[C@H]4CC(=O)NC4
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| InChi Key |
ZQPDJCIXJHUERQ-QWRGUYRKSA-N
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| InChi Code |
InChI=1S/C20H22ClFN6O2/c1-4-30-18-12(6-13(21)17(22)16(18)11-5-14(29)24-7-11)10(3)28-20-15(9(2)27-28)19(23)25-8-26-20/h6,8,10-11H,4-5,7H2,1-3H3,(H,24,29)(H2,23,25,26)/t10-,11-/m0/s1
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| Chemical Name |
(4R)-4-{3-[(1S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one
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| Synonyms |
INCB50465 HCl INCB-050465INCB-50465 INCB 050465 INCB 50465 IINCB050465 INCB050465 free base
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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 : ~125 mg/mL (~288.76 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 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 5: ≥ 2.08 mg/mL (4.81 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3101 mL | 11.5505 mL | 23.1011 mL | |
| 5 mM | 0.4620 mL | 2.3101 mL | 4.6202 mL | |
| 10 mM | 0.2310 mL | 1.1551 mL | 2.3101 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.
Parsaclisib Plus the Standard Drug Therapy in Patients with Newly Diagnosed, High Risk Diffuse Large B-cell Lymphoma
CTID: NCT04323956
Phase: Phase 1 Status: Active, not recruiting
Date: 2024-09-19
Products are for research use only; We do not sell to patients
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