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PIK-293 (IC87114 analog), the parent compound of PIK-294, is a novel, potent, and the first isoform-selective PI3K (phosphatidylinositol 3-kinase) inhibitor with with potential anticancer activity. It is 500-, 100- and 50-fold less potent than PI3Kα/β/γ to inhibit PI3Kδ with an IC50 of 0.24 M.
| Targets |
PI3Kδ (IC50 = 0.24 μM); PI3Kβ (IC50 = 10 μM); PI3Kγ (IC50 = 25 μM); PI3Kα (IC50 = 100 μM)
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|---|---|
| ln Vitro |
Kinase Assay: PIK-293 is a PI3K inhibitor, mostly for PI3Kδ with IC50 of 0.24 μM, 500-, 100- and 50-fold less potent to PI3Kα/β/γ, respectively. PIK-293 inhibits the p110α, p110β, p110δ, and p110γ with IC50 of 100 μM, 25 μM, 0.24 μM,and 10 &kkkmu;M. PIK-293 is the parent compound of PIK-294. |
| ln Vivo |
N/A
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| Enzyme Assay |
Protein and lipid kinases were expressed, purified, and subjected to in vitro kinase assays to determine IC50 values. See Supplemental Experimental Procedures for additional details.[1]
PIK-293 is a PI3K inhibitor. With an IC50 of 0.24 μM and being 500-, 100- and 50-fold less potent than PI3Kα/β/γ, respectively. The IC50 values for PIK-293 are 100 μM, 25 μM, 0.24 μM,and 10 &kkkmu;M for the inhibition of p110α, p110β, p110δ, and p110γ. Its parent substance, PIK-293 is the parent compound of PIK-294. |
| Cell Assay |
PI3-K Pathway Western Blotting[1]
Adipocytes or myotubes were serum-starved overnight. Cells were then preincubated with inhibitor (30 min), stimulated with insulin (100 nM, 5 min), and lysed. These lysates were resolved by SDS-PAGE, transferred to nitrocellulose, and analyzed by Western blotting. 32P-Orthophosphate Lipid Profiling[1] Metabolic labeling was performed essentially as described (Serunian et al., 1991). Cells were serum-starved overnight, incubated in phosphate-free medium (2 hr), and then labeled (2 hr) with 32P-orthophosphate. After this labeling, inhibitors were added to their final concentration (10 min) and then treated with insulin (100 nM, 10 min). Cells were lysed, the lipids extracted and deacylated, and analyzed by HPLC. Glucose Uptake[1] Glucose uptake in adipocytes was measured essentially as described (Lakshmanan et al., 2003). Adipocytes in 12-well plates were serum-starved (3 hr) and then incubated in PBS with compound (30 min), at which point cells were stimulated with insulin (100 nM). (3H)-2-deoxyglucose (100 μM,1 μCi/ml) was added 15 min after insulin stimulation and uptake was allowed to proceed for an additional 15 min. Adipocytes were washed three times with PBS, dissolved in 0.1% SDS, and the internalized radioactivity was measured by scintillation counting. |
| References | |
| Additional Infomation |
Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.[1]
PIK-39 itself does not possess a suitable site for chemical derivatization in this region, but modeling indicates that by replacing the adenine of IC87114 with the isosteric pyrazolopyrimidine (PIK-293, Figure 3A), aromatic substituents may be projected from C3 of this compound into the affinity pocket. We therefore synthesized the pyrazolopyrimidine analog of IC87114 (PIK-293) as well as a novel analog that contains a m-phenol at this position (PIK-294, Figure 3A). PIK-294 was designed, in part, based on the observation that one of the most potent inhibitors in our panel (PI-103) also projects a m-phenol into this region (Figure 2D). These compounds were then tested for inhibition of the class I PI3-Ks. We find that PIK-294 is 20- to 60-fold more potent than the parent compound, PIK-293, making PIK-294 one of the most potent p110δ-selective inhibitors that has been reported (Figure 3A). The successful design of this compound supports a conserved binding orientation for this chemotype across all PI3-Ks.[1] |
| Molecular Formula |
C22H19N7O
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|---|---|
| Molecular Weight |
397.432563066483
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| Exact Mass |
397.165
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| Elemental Analysis |
C, 66.49; H, 4.82; N, 24.67; O, 4.03
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| CAS # |
900185-01-5
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| Related CAS # |
900185-01-5
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| PubChem CID |
53245636
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
657.3±65.0 °C at 760 mmHg
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| Flash Point |
351.3±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.759
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| LogP |
2.18
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
684
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N(C2C(C)=CC=CC=2)C(CN2C3C(=C(N)N=CN=3)C=N2)=NC2C=CC=C(C1=2)C
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| InChi Key |
KQDBVHKNIYROHU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19N7O/c1-13-6-3-4-9-17(13)29-18(27-16-8-5-7-14(2)19(16)22(29)30)11-28-21-15(10-26-28)20(23)24-12-25-21/h3-10,12H,11H2,1-2H3,(H2,23,24,25)
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| Chemical Name |
2-[(4-aminopyrazolo[3,4-d]pyrimidin-1-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one
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| Synonyms |
PIK293; PIK 293; 900185-01-5; PIK293; IC87114 analog; 2-((4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one; 2-[(4-aminopyrazolo[3,4-d]pyrimidin-1-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one; 2-({4-aminopyrazolo[3,4-d]pyrimidin-1-yl}methyl)-5-methyl-3-(2-methylphenyl)quinazolin-4-one; KQDBVHKNIYROHU-UHFFFAOYSA-N; MLS006010992; PIK-293
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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: 50~80 mg/mL (125.8~201.3mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.29 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 25.0 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. Solubility in Formulation 2: ≥ 1.25 mg/mL (3.15 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 12.5 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. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (3.15 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 | 2.5162 mL | 12.5808 mL | 25.1617 mL | |
| 5 mM | 0.5032 mL | 2.5162 mL | 5.0323 mL | |
| 10 mM | 0.2516 mL | 1.2581 mL | 2.5162 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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