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| Targets |
PI3K-IN-60 targets the p110gamma catalytic subunit of class IB PI3Kgamma, a lipid kinase that is primarily expressed in leukocytes and involved in immune cell signaling. By inhibiting PI3Kgamma, it blocks the conversion of PIP2 to PIP3, thereby suppressing downstream signaling pathways including AKT/mTOR and NF-kappaB, which regulate immune cell migration, activation, and survival. Selective inhibition of PI3Kgamma over other PI3K isoforms (alpha, beta, delta) reduces off-target effects. The compound operates within the PI3K/AKT/mTOR signaling pathway and is relevant for inflammation, autoimmunity, and cancer research.
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| ln Vitro |
In vitro, PI3K-IN-60 inhibits PI3Kgamma enzymatic activity with an IC50 of 1.5 nM in a cell-free kinase assay using purified enzyme and a PI(3,4,5)P3 detection method. It shows >2,000-fold selectivity over PI3Kbeta and >600-fold selectivity over PI3Kalpha and PI3Kdelta. In functional cellular assays using immune cells (e.g., macrophages, neutrophils), the compound blocks chemotaxis and production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6) with EC50 values in the low nanomolar range. It also inhibits migration of pancreatic cancer cells and breast cancer cell lines at concentrations of 10-100 nM. No cytotoxicity is observed in normal cells up to 10 uM.
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| ln Vivo |
In vivo, PI3K-IN-60 (100 mg/kg, oral) inhibits tumor growth in a 4T1 murine mammary cancer model. In an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, oral administration at 20 or 80 mg/kg decreases disease severity and delays onset. It also reduces inflammatory cell infiltration into the central nervous system and suppresses levels of pro-inflammatory cytokines in serum and spinal cord. The compound is well-tolerated at these doses with no significant body weight loss reported. Dosing schedule: daily or every other day for 2-4 weeks. Formulation: 10% DMSO/40% PEG300/5% Tween 80/45% saline.
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| Enzyme Assay |
For non-cellular PI3Kgamma activity assay, use recombinant human PI3Kgamma (p110gamma/p101) at 1-2 nM in assay buffer (20 mM HEPES pH 7.4, 1 mM EGTA, 5 mM MgCl2, 0.1% CHAPS, 2 mM DTT). Incubate enzyme with PI3K-IN-60 (0.001-1000 nM, 10-point 3-fold dilutions, DMSO ≤1%) for 15 min at 25degC. Add substrate PIP2 (100 uM) and ATP (10 uM) and incubate for 30 min at 37degC. Stop reaction with 10% TCA, centrifuge, and detect PIP3 product by competitive ELISA or by ADP-Glo luminescence. Calculate IC50 using four-parameter logistic regression. Positive control: PI3Kgamma inhibitor AS-605240 (IC50 8 nM). Negative control: DMSO only.
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| Cell Assay |
For in vitro cell chemotaxis assay, isolate primary mouse neutrophils or macrophages, or use immune cell lines (e.g., RAW264.7 macrophages, THP-1 monocytes). Seed cells in upper chamber of transwell plate (5 um pore size) at 1×10⁵ cells/well in serum-free RPMI. Add PI3K-IN-60 at 0.1-1000 nM to both chambers. Add chemoattractant (e.g., C5a, fMLP, or SDF-1alpha, 10-100 nM) to lower chamber. Incubate for 2-4 h at 37degC. Count cells that migrated to lower chamber by crystal violet staining or flow cytometry. Calculate IC50 from inhibition curve. For cytokine production, culture RAW264.7 cells with 1 uM compound for 1 h, then stimulate with LPS (100 ng/mL, 6 h). Collect supernatant and measure TNF-alpha and IL-6 by ELISA. All experiments in triplicate; DMSO ≤0.1%.
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| Animal Protocol |
For in vivo EAE model, female C57BL/6 mice (6-8 weeks, n=10/group) are immunized subcutaneously with MOG35-55 peptide (100 ug) emulsified in CFA containing 4 mg/mL Mycobacterium tuberculosis, plus pertussis toxin (200 ng) intraperitoneally on day 0 and day 2. Starting at day 0, administer PI3K-IN-60 by oral gavage at 20 or 80 mg/kg once daily for 30 days. Formulate in 10% DMSO, 40% PEG300, 5% Tween 80, 45% saline (2-8 mg/mL). Score clinical signs daily: 0=normal, 1=limp tail, 2=hindlimb weakness, 3=hindlimb paralysis, 4=forelimb paralysis, 5=moribund/death. Collect spinal cords at endpoint for H&E and Luxol fast blue staining to assess inflammation and demyelination. Measure serum cytokines by ELISA. Vehicle control group receives same volume of vehicle. For 4T1 breast cancer model, female BALB/c mice (6-8 weeks) are injected orthotopically with 1×10⁵ 4T1 cells into mammary fat pad. When tumors reach 100 mm3 (day 10-14), treat with compound 100 mg/kg oral daily for 3 weeks. Monitor tumor volume (calipers) and body weight. Compare to vehicle control.
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| ADME/Pharmacokinetics |
PI3K-IN-60 is orally active and has favorable pharmacokinetic properties. Specific parameters (Cmax, Tmax, t½, AUC) are not publicly detailed, but efficacy in mouse models following oral administration (20-100 mg/kg) confirms oral bioavailability. The compound has molecular weight 441.55 and LogP estimated ~3-4, consistent with moderate to good absorption. Half-life (t½) is estimated to be 2-6 hours, supporting daily or every-other-day dosing. Volume of distribution (Vd) likely >1 L/kg, indicating tissue distribution. Clearance (CL) is likely hepatic via CYP450 metabolism. Protein binding not reported. For storage, powder at -20degC for up to 3 years; in DMSO at -80degC for 1 year. Formulation for in vivo: 10% DMSO/40% PEG300/5% Tween 80/45% saline.
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| Toxicity/Toxicokinetics |
No formal toxicity data published for PI3K-IN-60. In animal studies (EAE and 4T1 models), doses up to 100 mg/kg oral were well-tolerated with no significant body weight loss or gross signs of toxicity. As a PI3Kgamma inhibitor, potential on-target adverse effects may include immunosuppression (increased susceptibility to infections) and altered lipid metabolism, but these have not been reported for this compound. Standard laboratory safety precautions should be followed: avoid inhalation, ingestion, skin/eye contact; use PPE (gloves, lab coat, safety goggles); work in a fume hood. For research use only-not for human therapeutic use. Dispose of waste according to local regulations.
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| References | |
| Additional Infomation |
CAS: 2504036-13-7. Molecular formula: C22H27N5O3S, molecular weight: 441.55. Synonyms: PI3-Kinase Inhibitor, EX-A5492. Purity typically >98% by HPLC. Appearance: yellow solid. Solubility: DMSO (10 mM). Storage: powder -20degC for 3 years. Target: PI3Kgamma. IC50: 1.5 nM (PI3Kgamma). Selectivity: >600-fold over PI3Kalpha, delta; >2,000-fold over PI3Kbeta. Research areas: autoimmune diseases (multiple sclerosis), breast cancer, pancreatic cancer. Pathway: PI3K/AKT/mTOR. Not for human use. For research only.
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| Molecular Formula |
C22H27N5O3S
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| Molecular Weight |
441.55
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| Exact Mass |
441.183
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| CAS # |
2504036-13-7
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| PubChem CID |
155194179
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| Appearance |
Typically exists as solids at room temperature
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| Hydrogen Bond Donor Count |
1
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
701
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(SC(=N1)NC(=O)C)C2=NC(=C3C(=C2)CN(C3=O)[C@@H](C)C4CC4)N5CCOCC5
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| InChi Key |
FEOYQQKILUILEH-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C22H27N5O3S/c1-12-19(31-22(23-12)24-14(3)28)17-10-16-11-27(13(2)15-4-5-15)21(29)18(16)20(25-17)26-6-8-30-9-7-26/h10,13,15H,4-9,11H2,1-3H3,(H,23,24,28)/t13-/m0/s1
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| Chemical Name |
N-[5-[2-[(1S)-1-cyclopropylethyl]-4-morpholin-4-yl-3-oxo-1H-pyrrolo[3,4-c]pyridin-6-yl]-4-methyl-1,3-thiazol-2-yl]acetamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2647 mL | 11.3237 mL | 22.6475 mL | |
| 5 mM | 0.4529 mL | 2.2647 mL | 4.5295 mL | |
| 10 mM | 0.2265 mL | 1.1324 mL | 2.2647 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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