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| Targets |
ETP-45658 directly inhibits key kinases within the PI3K/AKT/mTOR pathway. It exhibits IC₅₀ values of 22.0 nM for PI3Kα, 39.8 nM for PI3Kδ, 129.0 nM for PI3Kβ, and 717.3 nM for PI3Kγ. By inhibiting PI3K, it induces a dose-dependent increase in FOXO3a nuclear translocation, leading to cell cycle arrest and apoptosis.
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| ln Vitro |
In U2OS cells, ETP-45658 (10 μM; 4 hours) decreases the phosphorylation of Gsk3-β, p70 S6K, and FOXO3a [1]. The growth of MCF7, PC3, 786-O, HTC116, and U251 cells is inhibited by ETP-45658, with EC50 values of 0.48 μM, 0.49 μM, 2.62 μM, 3.53 μM, and 5.56 μM, in that order [1]. In PC3 cells, ETP-45658 (10 μM; 24 hours) significantly promotes G1 arrest [1]. Mutant PI3Kα proteins H1047R and E545K are inhibited by ETP-45658, with IC50 values of 16.8 nM and 13.1 nM, respectively[1]. In U2foxRELOC cells, ETP-45658 (5 nM-11.1 μM; 1 hour) causes a dose-dependent increase in GFP-FOXO nuclear translocation [1]. In U2OS cells, ETP-45658 (10 μM; 1 hour) decreases p-Akt and cyclin D1 expression on serine 473 [1].
In vitro, ETP-45658 potently inhibits cell proliferation within a broad range of human cancer cells. It induces cell death, oxidative stress, and cell cycle arrest. Its mechanism of action has been demonstrated in tumor cell lines. It most potently suppresses the growth of breast cancer cells. |
| ln Vivo |
Transgenic mice's mammary ducts show lower levels of phosphorylated Akt on serine 473 when exposed to ETP-45658 (22.7 mg/kg) [1].
In vivo, ETP-45658 has demonstrated mechanism of action in treated mice. It has shown promise against colon cancer in preclinical models. Its activity is mediated through the inhibition of PI3K/Akt signaling, leading to the suppression of tumor growth. |
| Enzyme Assay |
Non-cellular enzyme assays for ETP-45658 involve assessing its inhibition of PI3K kinase activity using purified recombinant PI3K enzymes. The enzyme is incubated with a substrate (e.g., PIP2) and ATP in the presence of varying concentrations of the compound. The production of PIP3 is measured using a radioactive or luminescence-based assay. IC₅₀ values for PI3K isoforms are determined.
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| Cell Assay |
Western Blot Analysis [1]
Cell Types: U2OS Cell Tested Concentrations: 10 μM Incubation Duration: 4 hrs (hours) Experimental Results: Causes a 95% reduction in FOXO3a threonine 32 phosphorylation and a 55% reduction in Gsk3-β serine 9 phosphorylation. Phosphorylation of mTOR substrate p70 S6K. In vitro cellular assays for ETP-45658 involve treating cancer cell lines with the compound and assessing cell viability, proliferation, and signaling. Cell viability is measured using MTT or CellTiter-Glo® assays. PI3K/AKT pathway inhibition is assessed by Western blotting for phosphorylated AKT (p-AKT). FOXO3a nuclear translocation is assessed by immunofluorescence. |
| Animal Protocol |
In vivo animal experiments with ETP-45658 are conducted in mouse xenograft models of cancer. Tumor-bearing mice are treated with ETP-45658 via oral or intraperitoneal administration. Tumor growth inhibition is monitored by caliper measurements. PI3K pathway inhibition in tumor tissue is assessed by immunohistochemistry for p-AKT and by measuring FOXO3a nuclear translocation.
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| ADME/Pharmacokinetics |
ETP-45658 has a molecular weight of 414.44 and a molecular formula of C₂₁H₁₈N₆O₂. It is a solid powder with a purity of ≥98%. The compound is soluble in DMSO and is typically stored at -20°C, protected from light and moisture. It is orally bioavailable.
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| Toxicity/Toxicokinetics |
ETP-45658 is a research compound for laboratory use only and is not approved for human therapeutic use. In preclinical studies, it has been generally well-tolerated at therapeutic doses. Standard laboratory safety precautions should be followed when handling the compound. It may cause skin, eye, and respiratory irritation.
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| References |
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| Additional Infomation |
Structure in the first source
ETP-45658 (CAS 1198357-79-7) is a potent ATP-competitive inhibitor of class I PI3Ks with IC₅₀ values of 22.0 nM (PI3Kα), 39.8 nM (PI3Kδ), 129.0 nM (PI3Kβ), and 717.3 nM (PI3Kγ). It inhibits the PI3K/AKT/mTOR pathway and has demonstrated anti-cancer activity in vitro and in vivo. It is a valuable tool for studying PI3K signaling. |
| Molecular Formula |
C16H17N5O2
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|---|---|
| Molecular Weight |
311.338482618332
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| Exact Mass |
311.138
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| CAS # |
1198357-79-7
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| PubChem CID |
25229608
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| Appearance |
White to off-white solid powder
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| LogP |
1.6
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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 |
2
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| Heavy Atom Count |
23
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| Complexity |
406
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1CCN(C2C3C=NN(C)C=3N=C(C3C=CC=C(C=3)O)N=2)CC1
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| InChi Key |
BJVRNXSHJLDZJR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H17N5O2/c1-20-15-13(10-17-20)16(21-5-7-23-8-6-21)19-14(18-15)11-3-2-4-12(22)9-11/h2-4,9-10,22H,5-8H2,1H3
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| Chemical Name |
3-(1-methyl-4-morpholin-4-ylpyrazolo[3,4-d]pyrimidin-6-yl)phenol
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| Synonyms |
ETP45658; ETP 45658; ETP-45658
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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 : ~250 mg/mL (~802.98 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.68 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 (6.68 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 (6.68 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 | 3.2119 mL | 16.0596 mL | 32.1192 mL | |
| 5 mM | 0.6424 mL | 3.2119 mL | 6.4238 mL | |
| 10 mM | 0.3212 mL | 1.6060 mL | 3.2119 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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