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| Targets |
Parsaclisib HCl targets phosphoinositide 3-kinase delta (PI3Kδ), a Class I PI3K isoform that 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. It also shows selectivity over 57 other kinases.
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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 Ramos Burkitt lymphoma cell lines, parsaclisib (0.1-1000 nM; 2 h) inhibits anti-IgM-induced pAKT (Ser473) with an IC50 of 1 nM [2]. With an IC50 ranging from 0.2 to 1.7 nM, parsaclisib inhibits the proliferation of primary B cells in humans, dogs, rats, and mice upon activation of these receptors [2].
In vitro, Parsaclisib HCl potently inhibits PI3Kδ with an IC50 of 1 nM at 1 mM ATP. It shows approximately 20,000-fold selectivity for PI3Kδ over PI3Kα, PI3Kβ, and PI3Kγ, and over 57 other kinases. The compound inhibits the proliferation of primary human B cells and cytokine production in memory T cells. |
| 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 HCl synergizes with PIM protein kinase inhibition to cause tumor regression in models of 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 HCl involve PI3K kinase activity assays using purified recombinant PI3K isoforms. IC50 values are determined for PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ using radiolabeled ATP or luminescent kinase assays. Selectivity is confirmed by screening against a panel of 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 cell Tested Concentrations: 0.1-3000 nM Incubation Duration: 4 days Experimental Results: Maximum inhibition rate of four MCL cell lines was 70-90%, IC50 ≤ 10 nM. Pfeiffer, SU-DHL-5, SU-DHL-6, and WSU-NHL are highly sensitive, with IC50s ranging from 2 to 8 nM. In vitro cell-based assays for Parsaclisib HCl use primary human B cells and memory T cells. Cells are treated with the compound, and proliferation is measured by [³H]-thymidine incorporation. Cytokine production is measured by ELISA. 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 HCl have been conducted in mouse models of DLBCL. Tumor-bearing mice are treated with Parsaclisib HCl alone or in combination with PIM inhibitors, and tumor growth inhibition is monitored. Pharmacodynamic markers such as AKT phosphorylation are measured in tumor tissues. |
| ADME/Pharmacokinetics |
Parsaclisib HCl has a molecular formula of C20H23Cl2FN6O2 and a molecular weight of 469.34 g/mol. The chemical name is 4-[3-(1-{4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl}ethyl)-5-chloro-2-ethoxy-6-fluorophenyl]pyrrolidin-2-one. The compound is soluble in DMSO (150 mg/mL) and water (100 mg/mL).
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| Toxicity/Toxicokinetics |
Specific toxicological data for Parsaclisib HCl are not extensively detailed in the available literature. The compound has been evaluated in clinical trials for relapsed or refractory B-cell malignancies. As a PI3Kδ inhibitor, potential toxicities may include immunosuppression and gastrointestinal effects.
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| References |
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| Additional Infomation |
Parsaclisib hydrochloride is the hydrochloride form of Parsaclisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K) delta isoform with potential antitumor activity. Parsaclisib inhibits the PI3K delta isoform, thereby preventing the activation of the PI3K/AKT signaling pathway. This both reduces the proliferation of PI3K-delta-overexpressing tumor cells and induces their death. Unlike other PI3K isoforms, PI3K-delta is primarily expressed in hematopoietic diseases and cell lineages. Targeted inhibition of PI3K-delta 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 Treatment of myelofibrosis Parsaclisib HCl (CAS 1995889-48-9) is the hydrochloride salt of Parsaclisib, a potent and selective PI3Kδ inhibitor with an IC50 of 1 nM. It shows approximately 20,000-fold selectivity over PI3Kα, PI3Kβ, and PI3Kγ. The compound is orally active and synergizes with PIM inhibition in DLBCL models. No approved indication data are available. |
| Molecular Formula |
C20H23CL2FN6O2
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| Molecular Weight |
469.340025186539
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| Exact Mass |
468.124
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| Elemental Analysis |
C, 51.18; H, 4.94; Cl, 15.11; F, 4.05; N, 17.91; O, 6.82
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| CAS # |
1995889-48-9
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| Related CAS # |
Parsaclisib;1426698-88-5
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| PubChem CID |
122507744
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
632
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1C=C(C(=C(C=1F)[C@H]1CC(NC1)=O)OCC)[C@H](C)N1C2C(=C(N)N=CN=2)C(C)=N1.Cl
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| InChi Key |
TWHUONANZMKBKX-ACMTZBLWSA-N
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| InChi Code |
InChI=1S/C20H22ClFN6O2.ClH/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)1H/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
hydrochloride
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| Synonyms |
INCB50465 HCl INCB-050465INCB-50465 INCB050465 HClINCB 50465 INCB 050465 Parsaclisib HCl
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~240 mg/mL (~511.36 mM)
H2O : ~100 mg/mL (~213.07 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6 mg/mL (12.78 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.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 6 mg/mL (12.78 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 60.0 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. View More
Solubility in Formulation 3: ≥ 6 mg/mL (12.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (106.53 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1307 mL | 10.6533 mL | 21.3065 mL | |
| 5 mM | 0.4261 mL | 2.1307 mL | 4.2613 mL | |
| 10 mM | 0.2131 mL | 1.0653 mL | 2.1307 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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