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| Targets |
PI4KIIα 0.47 μM (IC50)
PI-273 targets PI4KIIα (phosphatidylinositol 4-kinase type II alpha), a kinase that catalyzes the phosphorylation of phosphatidylinositol to phosphatidylinositol 4-phosphate (PI4P). PI4P is a key signaling lipid involved in various cellular processes including membrane trafficking, signal transduction, and cell growth. By inhibiting PI4KIIα, PI-273 reduces PI4P levels, cell viability, and AKT signaling in cells. The compound is highly selective for PI4KIIα, as demonstrated by the lack of effect in PI4KIIα knockout cells. This mechanism is particularly relevant for cancers with dysregulated PI4KIIα signaling. |
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| ln Vitro |
At the G2-M phase, PI-273 (2 μM; 48 hours) inhibits the cell cycle[1]. All three Ras wild-type breast cancer cells (MCF-7, T-47D, and SK-BR-3) undergo cell apoptosis when exposed to PI-273 (2 μM) for 48 hours[1]. AKT signaling pathway suppression is possible with PI-273 (0.5-2 μM; for 3 days) in a dose- and time-dependent way[1]. Both MCF-7 and T-47D cell proliferation is inhibited in a time-dependent manner by PI-273 at 1 μM and 2 μM [1].
In vitro, PI-273 inhibits PI4KIIα kinase activity with an IC50 of 0.47 μM and suppresses cell proliferation. The compound reduces PI4P levels, cell viability, and AKT signaling in wild-type MCF-7 cells but not in PI4KIIα-knockout MCF-7 cells, demonstrating its high selectivity for PI4KIIα. PI-273 inhibits breast cancer cell proliferation, blocks the cell cycle, and induces cell apoptosis. These in vitro studies demonstrate the compound's potential as an anticancer agent. |
| ln Vivo |
In MCF-7 xenografts, PI-273 (intraperitoneal injection; 25 mg/kg/day; 15 days) significantly inhibits the tumor weight and volume[1]. The absolute bioavailability of PI-273 is 5.1%[1]. Its half-lives are 0.411 hours for intravenous treatment and 1.321 hours for intragastric administration (0.5 mg/kg intravenously or 1.5 mg/kg intragastrically; 0.08-5 hours).
In vivo, PI-273 has been studied for its potential in cancer therapy, particularly in breast cancer. The compound's ability to inhibit PI4KIIα and reduce tumor growth suggests potential therapeutic applications for cancers with dysregulated PI4KIIα signaling. Further in vivo studies are needed to evaluate its efficacy and safety. |
| Enzyme Assay |
The in vitro enzyme inhibition assay for PI-273 measures its ability to inhibit PI4KIIα kinase activity. The assay is performed using purified PI4KIIα enzyme and phosphatidylinositol as substrate, with radiolabeled ATP. The reaction is monitored by measuring the incorporation of radioactive phosphate into PI4P or by other suitable methods. IC50 values are calculated from dose-response curves. Selectivity is assessed by testing the compound against other lipid kinases and related enzymes.
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| Cell Assay |
Cell Cycle Analysis[1]
Cell Types: MCF-7, T-47D, SK-BR-3, MDA-MB-231, SUM229PE, Hs 578T cells Tested Concentrations: 2 μM Incubation Duration: 48 hrs (hours) Experimental Results: Blocked the cell cycle at the G2-M phase. Apoptosis Analysis[1] Cell Types: MCF-7, T-47D, and SK-BR-3 cells Tested Concentrations: 2 μM Incubation Duration: 48 hrs (hours) Experimental Results: Induced cell apoptosis in all three Ras wild-type breast cancer cells: MCF-7, T-47D, and SK-BR-3. Western Blot Analysis[1] Cell Types: MCF-7 cells Tested Concentrations: 0.5, 1, 2 μM Incubation Duration: For 3 days Experimental Results: Suppressed the AKT signaling pathway in a dose- and time-dependent manner. In vitro cellular studies are conducted using breast cancer cell lines, particularly MCF-7 cells. Cells are treated with PI-273 at various concentrations (typically μM ranges) for defined time periods. Cell viability is assessed using MTT or CellTiter-Glo assays. PI4P levels are measured by lipid extraction and mass spectrometry or ELISA. AKT signaling is evaluated by Western blot. Cell cycle analysis and apoptosis assays are performed to evaluate mechanisms of cell death. |
| Animal Protocol |
Animal/Disease Models: Eightweeks old male BALB/c nude mice with MCF-7 cell[1]
Doses: 25 mg/kg Route of Administration: intraperitoneal (ip)injection; daily; 15 days Experimental Results: Suppressed the tumor volume and weight in the MCF-7 xenografts. Animal/Disease Models: Male SD (Sprague-Dawley) rats[1] Doses: 0.5 mg/kg (intravenously (iv)) or 1.5 mg/kg (intragastrically (po)) (pharmacokinetic/PK Study) Route of Administration: intravenously (iv) or intragastrically (po); 0.08, 0.16, 0.33, 0.67, 1, 1.5, 2, 3 and 5 hrs (hours) Experimental Results: Has a half-life of 0.411 hrs (hours) for intravenous (iv)administration and 1.321 hrs (hours) for intragastric (po)administration, and the absolute bioavailability of PI-273 is 5.1 %. In vivo animal experiments are performed using xenograft models of breast cancer. Tumor-bearing mice are administered PI-273 via various routes at different doses. Tumor volume is measured over time, and endpoints include tumor growth inhibition and survival. Pharmacodynamic studies evaluate PI4KIIα inhibition and downstream signaling in tumor tissues. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of PI-273 include solubility in DMSO. The compound has a molecular weight of 381.89 g/mol and molecular formula C16H16ClN3O2S2. Purity is ≥98%. Storage conditions should follow the manufacturer's recommendations. The compound should be protected from light and moisture. For in vivo administration, appropriate formulations should be used.
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| Toxicity/Toxicokinetics |
Toxicological data for PI-273 are derived from preclinical studies. The compound is for research use only and not intended for human therapeutic applications. No significant toxicity has been reported at effective doses in vitro. Standard safety precautions should be followed when handling the compound. Long-term toxicity and carcinogenicity studies have not been conducted.
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| References | |
| Additional Infomation |
PI4KIIα inhibitors; structures can be found in the first article.
PI-273 is the first reversible and specific inhibitor of PI4KIIα with an IC50 of 0.47 μM. It inhibits breast cancer cell proliferation, blocks the cell cycle, and induces cell apoptosis. The compound is highly selective for PI4KIIα, as demonstrated by the lack of effect in PI4KIIα knockout cells. PI-273 is particularly valuable in research focused on cancers with overexpressed MDM2, where p53 function is often compromised. It has the molecular formula C16H16ClN3O2S2 and molecular weight of 381.89 g/mol. |
| Molecular Formula |
C16H16CLN3O2S2
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|---|---|
| Molecular Weight |
381.900139808655
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| Exact Mass |
381.037
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| CAS # |
925069-34-7
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| PubChem CID |
17168969
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
498
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C(CC)=C(C)SC=1NC(NC(C1C=CC(Cl)=CC=1)=O)=S)N
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| InChi Key |
MIERMBQDBLFAFW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H16ClN3O2S2/c1-3-11-8(2)24-15(12(11)13(18)21)20-16(23)19-14(22)9-4-6-10(17)7-5-9/h4-7H,3H2,1-2H3,(H2,18,21)(H2,19,20,22,23)
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| Chemical Name |
2-[(4-chlorobenzoyl)carbamothioylamino]-4-ethyl-5-methylthiophene-3-carboxamide
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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 : 6.02 mg/mL (15.76 mM)
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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 | 2.6185 mL | 13.0924 mL | 26.1849 mL | |
| 5 mM | 0.5237 mL | 2.6185 mL | 5.2370 mL | |
| 10 mM | 0.2618 mL | 1.3092 mL | 2.6185 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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