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Purity: ≥98%
PIK-108 (PIK108) is a novel, potent and allosteric inhibitor of p110β/p110δ, lipid modifying kinases, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits β and δ (PI3Kβ/δ).
| Targets |
PIK-108 is a morpholinochromone compound that inhibits phosphoinositide 3-kinases (PI3-Ks). It belongs to the chromone class of PI3-K inhibitors that target p110β and p110δ. Based on structural modeling, it contains the key aryl morpholine pharmacophore found in LY294002, where the oxygen atom in the morpholine ring makes a critical hydrogen bond to the backbone amide of Val882 (p110γ numbering) [1].
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| ln Vitro |
One hour of PIK-108 (0.1–10 μM) prevents PKB/Akt phosphorylation [1].
PIK-108 is one of the chromone-based inhibitors (along with TGX-115 and TGX-286) that target p110β and p110δ. The biochemical selectivity analysis shown in Figure 1B indicates that chromone compounds like TGX-115 and TGX-286 (which are from the same chemotype as PIK-108) potently inhibit p110β and p110δ while showing reduced activity against other class I PI3-K isoforms. Specific IC50 values for PIK-108 are not provided in the text, but the chromone class is characterized as having selectivity for p110β/p110δ [1]. Structural modeling based on the LY294002 structure suggests that PIK-108 projects large aromatic substituents toward the induced pocket observed in the PIK-39 structure (the region around Met804). This interaction with the selectivity pocket may explain how chromone compounds achieve their isoform selectivity. The modeling indicates that PIK-108 may achieve its selectivity through unique interactions in this region, either by occupying a similar induced pocket as PIK-39 or by exploiting natural sequence differences in this region among PI3-K isoforms [1]. In functional cellular assays using 3T3-L1 adipocytes and L6 myotubes, chromone inhibitors (TGX-115 and TGX-286, which share the same chemotype as PIK-108) were tested for their effects on insulin signaling. The p110β/p110δ inhibitors had no effect on insulin-stimulated phosphorylation of Akt, p70S6K, rpS6, or other PI3-K pathway effectors. However, the p110β inhibitor TGX-115 reduced insulin-stimulated PI(3,4)P2 and PIP3 levels in adipocytes by approximately 50% yet failed to block Akt or mTORC1 activation, indicating that the PIP3 pool generated by p110β is not functionally coupled to Akt activation [1]. In IRS-1 immunoprecipitation assays from adipocytes and myotubes, the p110β/p110δ inhibitor TGX-115 (same chemotype as PIK-108) reduced IRS-1-associated PI3-K activity by approximately 30% in adipocytes and 10% in myotubes, confirming that p110β contributes to PIP3 production at the IRS-1 complex but this activity is not required for downstream signaling to Akt [1]. |
| ln Vivo |
In insulin tolerance tests in mice, the p110β/p110δ inhibitor TGX-115 (same chemotype as PIK-108) was tested at 10 mg/kg by intraperitoneal injection following insulin challenge. TGX-115 had no effect on blood glucose levels in response to insulin, in contrast to p110α inhibitors which completely protected animals from insulin-stimulated decline in blood glucose [1].
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| Enzyme Assay |
For biochemical characterization of PI3-K inhibitors, class I PI3-Ks (p110α, p110β, p110δ, p110γ) were expressed, purified, and subjected to in vitro kinase assays to determine IC50 values. The specific assay conditions and substrates are described in the Supplemental Experimental Procedures. Compounds were tested at varying concentrations, and IC50 values were calculated from dose-response curves [1].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Glioma cell line expressing wild-type PTEN Tested Concentrations: 0.1, 0.5, 1, 4 and 10 μM Incubation Duration: 1 hour Experimental Results: Demonstrated varying degrees of phosphorylation of PKB/Akt Inhibited, but demonstrated a tendency to inhibit PKB/Akt phosphorylation. PKB/Akt phosphorylation was more effectively diminished in mutant PTEN-expressing cell lines compared with wild-type PTEN-expressing cell lines. For studies in 3T3-L1 adipocytes and L6 myotubes, cells were serum-starved and then treated with inhibitors at various concentrations for 30-60 minutes prior to stimulation with insulin (100 nM) or LPA (10 μM). Cell lysates were prepared and analyzed by Western blotting using phospho-specific antibodies against Akt (Thr308, Ser473), p70S6K, rpS6, 4E-BP1, ERK1/2, and GSK3α/β [1]. For IRS-1 immunoprecipitation assays, cells were stimulated with insulin (100 nM) for 1.5, 5, or 30 minutes. IRS-1 was immunoprecipitated from cell lysates, and immunocomplexes were subjected to in vitro PI3-K assays. The contribution of each PI3-K isoform was determined by adding isoform-selective inhibitors (PIK-23 for p110δ, TGX-115 for p110β/p110δ, and PIK-75 for p110α) to the kinase reactions at concentrations that inhibit >90% of their primary target with minimal inhibition of other class I PI3-Ks [1]. For metabolic labeling experiments, cells were serum-starved overnight, incubated in phosphate-free medium for 2 hours, and then labeled with ³²P-orthophosphate for 2 hours. Inhibitors were added for 10 minutes, followed by insulin stimulation (100 nM, 10 minutes). Lipids were extracted, deacetylated, and analyzed by HPLC to quantify PI(3,4)P2 and PIP3 levels [1]. |
| Animal Protocol |
Four-month-old FVB/N female mice (n=5 per group) were fasted at 9:00 AM and then given human insulin (0.75 U/kg) or vehicle (PBS) intravenously at 12:00 PM. Immediately following insulin treatment, animals were given an intraperitoneal injection of inhibitor (10 mg/kg) or vehicle (50% DMSO). Blood glucose levels were measured with an AccuCheck Active glucose meter at 15-minute intervals after insulin injection [1].
Four-month-old FVB/N female mice (n=5 per group) were fasted at 9:00 AM and then given human insulin (0.75 U/kg) or vehicle (PBS) intravenously at 12:00 PM. Immediately following insulin treatment, animals were given an intraperitoneal injection of inhibitor (10 mg/kg) or vehicle (50% DMSO). Blood glucose levels were measured with an AccuCheck Active glucose meter at 15-minute intervals after insulin injection [1]. |
| References |
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| Additional Infomation |
See also: Pik-108 (Notes moved to).
PIK-108 belongs to the chromone class of PI3-K inhibitors, which are characterized by their selectivity for p110β and p110δ. These compounds contain the aryl morpholine pharmacophore that is critical for PI3-K binding, with the morpholine oxygen forming a hydrogen bond to the backbone amide of Val882 in the ATP binding pocket. Structural modeling suggests that chromone inhibitors achieve their isoform selectivity by projecting aromatic substituents toward the selectivity pocket near Met804, similar to the binding mode observed for the p110δ-selective inhibitor PIK-39 [1]. The chromone inhibitors (including TGX-115 and TGX-286, which share the same chemotype as PIK-108) have been valuable tools for dissecting the roles of p110β and p110δ in various biological processes. Studies using these inhibitors demonstrated that p110β and p110δ play a less significant role in insulin signaling in adipocytes and myotubes, with p110α being the primary insulin-responsive PI3-K. However, p110β does contribute to PIP3 production at the IRS-1 complex and sets a threshold for p110α activity in myotubes, as evidenced by dose-shift experiments where p110β inhibition increased the amount of p110α inhibitor required to block Akt phosphorylation. These findings have implications for the development of isoform-selective PI3-K inhibitors for therapeutic applications, suggesting that p110β-selective inhibitors may be less likely to cause insulin resistance [1]. |
| Molecular Formula |
C22H24N2O3
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|---|---|
| Molecular Weight |
364.437565803528
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| Exact Mass |
364.178
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| CAS # |
901398-68-3
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| Related CAS # |
901398-68-3
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| PubChem CID |
70686584
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| Appearance |
White to off-white solid powder
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
552
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2C=C(C)C=C(C=2OC(N2CCOCC2)=C1)C(C)NC1C=CC=CC=1
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| InChi Key |
VRCXIJAYLCUSHC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H24N2O3/c1-15-12-18(16(2)23-17-6-4-3-5-7-17)22-19(13-15)20(25)14-21(27-22)24-8-10-26-11-9-24/h3-7,12-14,16,23H,8-11H2,1-2H3
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| Chemical Name |
6-methyl-2-morpholino-8-(1-(phenylamino)ethyl)-4H-chromen-4-one
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| Synonyms |
PIK-108 PIK 108 PIK108.
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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 : ~50 mg/mL (~137.20 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.71 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 20.8 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: ≥ 2.08 mg/mL (5.71 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7439 mL | 13.7197 mL | 27.4394 mL | |
| 5 mM | 0.5488 mL | 2.7439 mL | 5.4879 mL | |
| 10 mM | 0.2744 mL | 1.3720 mL | 2.7439 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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