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Parsaclisib HCl (INCB-50465; INCB-050465), the hydrochloride salt of Parsaclisib, is a novel and potent PI3Kδ inhibitor which inhibits PI3Kδ with an IC50 of 1 nM at 1 mM ATP, and shows appr 20,000-fold selectivity for PI3Kα, PI3Kβ, PI3Kγ and 57 other kinases. INCB050465 synergizes with PIM protein kinase inhibition to cause tumor regression in a model of DLBCL. It displays potent activity with IC50 ranging from 0.2 to 2 nM. In addition, INCB050465 blocks the proliferation of several DLBCL and MCL cell lines in vitro (EC50 < 10 nM) and can slow tumor growth in the Pfeiffer model of DLBCL in vivo.
| 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].
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| 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].
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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. |
| 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. |
| References |
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| Additional Infomation |
Parsaclisib Hydrochloride is the hydrochloride salt form of parsaclisib, an inhibitor of the delta isoform of phosphoinositide-3 kinase (PI3K) with potential antineoplastic activity. Parsaclisib inhibits the delta isoform of PI3K and prevents the activation of the PI3K/AKT signaling pathway. This both decreases proliferation and induces cell death in PI3K-delta-overexpressing tumor cells. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic disease and cell lineages. The targeted inhibition of PI3K-delta is designed to preserve 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.
Drug Indication Treatment of myelofibrosis |
| 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) |
|---|---|
| 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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