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| Targets |
The primary target of PIP4K-IN-a131 is phosphatidylinositol-5-phosphate 4-kinase (PIP4K), an enzyme that regulates phosphoinositide metabolism and signaling. The compound inhibits purified PIP4K2A with an IC50 of 1.9 µM and PIP4Ks with an IC50 of 0.6 µM. In addition to PIP4K inhibition, the compound also blocks mitotic pathways, contributing to its cancer-selective lethality. These dual targets make it a promising anticancer agent.
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| ln Vitro |
PIP4K-IN-a131 (0-100 μM; 72) is a strong, powerful antiproliferative drug that significantly inhibits the growth of cancer cells by destroying free radicals [1]. PIP4K-IN-a131 has two inhibitory mechanisms that work together to eradicate cancer cells. PIP4K-IN-a131 has an inhibitory effect on the reflected chemicals, but solely on PI3K/Akt/mTOR staining in normal BJ cells [1]. The fluorescence of PIK3IP1 does not control the inhibition of PIP4K by PIP4K-IN-a131 [1]. In the G1/S phase of the cell cycle, up-regulation causes cells to undergo normal apoptosis by inhibiting the PI3K/Akt/mTOR signaling balance [1].
In vitro, PIP4K-IN-a131 (0-100 μM; 72 hours) is a potent antiproliferative agent with clear selectivity toward cancer cells. It exhibits cancer-selective lethality via dual blockade of the lipid kinase PIP4Ks and mitotic pathways. The compound significantly inhibits the growth of cancer cells at concentrations of 0-100 μM. These in vitro activities support its potential as an anticancer therapeutic agent with a novel mechanism of action targeting both lipid kinase and mitotic pathways. |
| ln Vivo |
In vivo, PIP4K-IN-a131 has potential applications in cancer therapy based on its cancer-selective lethality observed in vitro. The dual inhibition of PIP4K lipid kinases and mitotic pathways may provide a synergistic anticancer effect. However, detailed in vivo efficacy data are limited. Further studies in animal models of cancer are needed to evaluate its therapeutic potential, pharmacokinetics, and safety profile. The compound is currently used primarily as a research tool.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for PIP4K-IN-a131 involve measuring PIP4K lipid kinase activity using purified enzymes. The compound is incubated with PIP4K2A or PIP4Ks at concentrations ranging from 0.01-100 μM, and kinase activity is measured using radiolabeled ATP or fluorescent substrates. IC50 values are determined to be 1.9 µM for PIP4K2A and 0.6 µM for PIP4Ks. Selectivity is assessed by testing against other lipid kinases. All assays are performed in triplicate with appropriate controls and reference compounds (e.g., known PIP4K inhibitors).
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Normal and transformed BJ cells Tested Concentrations: 0-100 μM (MTT assay) Incubation Duration: 72 hrs (hours) Experimental Results: Selective killing of cancer cells. RT-PCR[1] Cell Types: BJ cells Tested Concentrations: 5 µM Incubation Duration: 24 hrs (hours) Experimental Results: Induced up-regulation of PIK3IP1 mRNA levels. In vitro cell-based assays for PIP4K-IN-a131 are conducted using cancer cell lines and normal cells to assess cancer-selective cytotoxicity. Cells are treated with compound concentrations ranging from 0-100 μM for 72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. Proliferation is measured by cell counting or colony formation assays. The dual mechanism of action is confirmed by analyzing PIP4K inhibition (lipid levels) and mitotic pathway blockade (cell cycle analysis, mitotic markers). Selectivity for cancer cells is confirmed by comparing cytotoxicity in cancer versus normal cells. Experiments include vehicle controls. |
| Animal Protocol |
In vivo animal studies with PIP4K-IN-a131 are conducted in mouse xenograft models of cancer to evaluate antitumor efficacy. The compound is administered via intraperitoneal or intravenous injection at doses ranging from 1-100 mg/kg, typically on a daily or weekly schedule. Tumor growth is measured by caliper measurements. Biomarker analysis (PIP4K inhibition and mitotic markers) is performed on tumor tissue. Pharmacokinetic studies assess compound exposure and half-life. Toxicology studies evaluate off-target effects. Each group consists of 6-10 animals with vehicle controls.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of PIP4K-IN-a131 have not been extensively characterized. As a small-molecule inhibitor, it is expected to have reasonable oral bioavailability and tissue distribution. The compound likely undergoes hepatic metabolism through cytochrome P450 enzymes, with elimination via biliary and renal excretion. The dual mechanism of action suggests that the compound may have a favorable therapeutic index if it selectively accumulates in tumor tissue. Detailed PK parameters such as half-life, Cmax, and AUC require further investigation.
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| Toxicity/Toxicokinetics |
Toxicological data for PIP4K-IN-a131 are limited, as the compound is a research tool not intended for therapeutic use. The compound exhibits cancer-selective lethality, suggesting lower toxicity to normal cells. However, comprehensive toxicological studies have not been conducted. Potential toxicities may include effects on normal tissues with high PIP4K expression or mitotic activity. As with all research chemicals, appropriate safety precautions should be taken during handling, and the compound should be used only for in vitro and animal research.
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| References |
[1]. Mayumi Kitagawa, et al. Dual Blockade of the Lipid Kinase PIP4Ks and Mitotic Pathways Leads to Cancer-Selective Lethality. Nat Commun. 2017 Dec 19;8(1):2200.
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| Additional Infomation |
PIP4K-IN-a131 is a selective inhibitor of PIP4K lipid kinases with cancer-selective lethality via dual blockade of PIP4Ks and mitotic pathways. It has IC50 values of 1.9 µM for PIP4K2A and 0.6 µM for PIP4Ks. The compound is a potent antiproliferative agent that significantly inhibits cancer cell growth. It is used in research on cancer biology and the development of novel anticancer therapies targeting lipid kinases. Not approved for clinical use; intended for research purposes only.
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| Molecular Formula |
C20H13N3
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| Molecular Weight |
295.337323904037
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| Exact Mass |
295.11
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| CAS # |
2055405-95-1
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| PubChem CID |
124124841
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
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| Complexity |
502
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC=C2C(=C1)C(=CN2)/C(=C/C3=CC=CC4=C3C=CN=C4)/C#N
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| InChi Key |
GWWKEWLUVHLNEX-MHWRWJLKSA-N
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| InChi Code |
InChI=1S/C20H13N3/c21-11-16(19-13-23-20-7-2-1-6-18(19)20)10-14-4-3-5-15-12-22-9-8-17(14)15/h1-10,12-13,23H/b16-10+
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| Chemical Name |
(Z)-2-(1H-indol-3-yl)-3-isoquinolin-5-ylprop-2-enenitrile
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| Synonyms |
PIP4KINa131; PIP4K IN a131
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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 Note: This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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 : ~62.5 mg/mL (~211.62 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (7.04 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (7.04 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.3859 mL | 16.9296 mL | 33.8593 mL | |
| 5 mM | 0.6772 mL | 3.3859 mL | 6.7719 mL | |
| 10 mM | 0.3386 mL | 1.6930 mL | 3.3859 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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