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Purity: ≥98%
Idelalisib (CAL-101, GS-1101; trade name Zydelig), an approved anticancer drug, is a potent and selective p110δ inhibitor with IC50 of 2.5 nM in cell-free assays; it has 40- to 300-fold greater selectivity for p110δ than p110α/β/γ, and 400- to 4000-fold more selectivity to p110δ than C2β, hVPS34, DNA-PK and mTOR. Phosphatidylinositol-3-kinase p110δ acts as a focal point for signaling from cell surface receptors that are known to support malignant B-cell survival and proliferation. Idelalisib thus has the potential to have anti-tumor and immunomodulating effects. The use of idelalisib to treat various blood cancers, including leukemia, received FDA and EMA approval in July 2014.
| Targets |
p110δ (IC50 = 2.5 nM); p110γ (IC50 = 89 nM); p110β (IC50 = 565 nM); p110α (IC50 = 820 nM); hVps34 (IC50 = 978 nM); DNA-PK (IC50 = 6729 nM)
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| ln Vitro |
Idelalisib (CAL-101; GS-1101) is a highly selective and potent inhibitor of p110δ (EC50=8 nM). While no activity is seen against a panel of 402 different kinases at 10 μM, greater selectivity (400- to 4000-fold) is seen against related kinases C2, hVPS34, DNA-PK, and mTOR. At 10 μM, CAL-101 only reduces PDGF-induced pAkt by 25%. With an EC50 of 1.9 μM, idelalisib (CAL-101) inhibits LPA-induced pAkt. While formyl-methionyl-leucyl-leucyl-phenylalanine activation of p110γ is inhibited with an EC50 of 3 μM, idelalisib (CAL-101) blocks FcRI p110δ-mediated CD63 expression with an EC50 of 8 nM. As a result, CAL-101 has a 240–2500-fold selectivity for p110δ over the other class I PI3K isoforms in cell-based assays[1]. CAL-101 When compared to vehicle treatment alone, idelalisib (CAL-101) induces a significant increase in the apoptosis of chronic lymphocytic leukemia (CLL) cells (P<0.001). Without regard to interphase cytogenetics or IgVH mutation status, idelalisib (CAL-101) causes selective cytotoxicity in CLL cells[2].
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| ln Vivo |
In the brain homogenates of both p110D910A/D910A mice and Idelalisib (CAL-101) (40 mg/kg, i.v.) post-treated mice, a significant decrease in CD11b+Ly6G+ neutrophils has been noted[3].
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| Enzyme Assay |
PI3K assay is preformed on whole-cell lysates from CLL or normal B cells. There is an ELISA test for PI3K. In a nutshell, PI(4,5)P2 substrate and reaction buffer containing adenosine triphosphate (ATP) are combined with whole-cell extracts, and the mixture is then left to incubate at room temperature. The addition of PI(3,4,5)P3 detector combined with EDTA (ethylenediaminetetraacetic acid) and an hour of incubation at room temperature stop the reaction. The mixture is then transferred from each well to a PI3K ELISA plate and given an additional hour to incubate. After washing, plates are incubated for 30 minutes with a secondary detector. After a second wash, the plates are added to with 3,3′,5,5′-tetramethylbenzidine solution for 5 minutes, after which H2SO4 is added to halt all reactions. A 96-well plate reader from Labsystems reads plates at 450 nm.
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| Cell Assay |
MTT assays are performed to determine cytotoxicity. Briefly, 1×105 cells (CLL B cells or healthy volunteer T cells or NK cells) are incubated for 48 hours with different concentrations of Idelalisib (CAL-101) (0.1 μM, 1 μM, 5 μM, 10 μM), 25 μM LY294002, or vehicle control. MTT reagent is then added. In a Labsystems plate reader, absorbance is measured using spectrophotometry at 540 nm after the addition of DMSO. An annexin/PI flow cytometry method is also used to determine the viability of cells at different time intervals. The software program Expo-ADC32 is used to analyze the data. For each sample, at least 10,000 cells are counted. The percentage of all positive cells compared to the untreated control is how the results are expressed. It was used in experiments to study caspase-dependent apoptosis along with 100 μM Z-VAD. The addition of 1 μg/mL CD40L, 800 U/mL IL-4, 50 ng/mL BAFF, 20 ng/mL TNF-α, or coculturing on fibronectin- or stromal (HS-5 cell line)-coated plates are some of the experiments used to study survival signals. A 75 cm2 flask (80%–100% confluent) is plated per 6-well plate for stromal coculture 24 hours before CLL cells are added[2].
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| Animal Protocol |
Mice: For Idelalisib (CAL-101) treatment, wild-type C57BL/6 mice are administered either 40 mg/kg Idelalisib (CAL-101) or vehicle DMSO, by 25 μL infusion into the femoral vein, 15 min before I/R (pre-treatment), or 3 and 6 h after initiation of reperfusion (post-treatment). The cerebral blood flow (CBF) of untreated animals and those given Idelalisib (CAL-101) was measured using a laser Doppler perfusion monitor. An 90-95% reduction in blood flow to the MCAO infarct region was observed in the CBF measurements taken right before and after MCAO, as well as again at 3 h after reperfusion. This reduction was consistent across groups.
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| References |
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| Molecular Formula |
C22H18FN7O
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|---|---|
| Molecular Weight |
415.42
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| Exact Mass |
415.1557
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| Elemental Analysis |
C, 63.61; H, 4.37; F, 4.57; N, 23.60; O, 3.85
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| CAS # |
870281-82-6
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| Related CAS # |
Idelalisib-d5;1830330-31-8
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| Appearance |
white solid powder
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| SMILES |
O=C1N(C2=CC=CC=C2)C([C@@H](NC3=C4N=CNC4=NC=N3)CC)=NC5=C1C(F)=CC=C5
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| Chemical Name |
(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
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| Synonyms |
GS1101; CAL-101; GS 1101; CAL101; GS-1101; CAL 101; Idelalisib; trade name Zydelig
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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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4072 mL | 12.0360 mL | 24.0720 mL | |
| 5 mM | 0.4814 mL | 2.4072 mL | 4.8144 mL | |
| 10 mM | 0.2407 mL | 1.2036 mL | 2.4072 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02135133 | Active Recruiting |
Drug: Idelalisib Drug: Ofatumumab/td> | Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma |
Dana-Farber Cancer Institute | June 2014 | Phase 2 |
| NCT03133221 | Active Recruiting |
Drug: Zydelig | Adult Solid Neoplasm | National Cancer Institute (NCI) |
June 27, 2011 | Phase 1 |
| NCT02389309 | Active Recruiting |
Follicular Lymphoma Drug: Temsirolimus |
Recurrent Brain Neoplasm B-cell Lymphoma |
University of Maryland, Baltimore |
October 23, 2017 | Phase 2 |
| NCT02457598 | Active Recruiting |
Drug: Idelalisib Drug: Tirabrutinib |
B-cell Malignancies | Gilead Sciences | June 16, 2015 | Phase 1 |
| NCT03283137 | Active Recruiting |
Drug: TGR-1202 Drug: Pembrolizumab |
CLL B-cell Non Hodgkin Lymphoma |
University of Chicago | January 23, 2018 | Phase 1 |
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