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| 5mg |
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| 10mg |
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| Targets |
The primary target of THZ-P1-2 is PI5P4K (phosphatidylinositol-5-phosphate 4-kinase), including the α, β, and γ isoforms. The compound covalently binds to cysteines on a disordered loop in PI5P4Kα/β/γ. It inhibits PI5P4Kα with an IC50 of 190 nM, PI5P4Kα with 0.95 μM, and PI5P4Kβ with 5.9 μM. By inhibiting PI5P4K, the compound disrupts autophagy and mitochondrial homeostasis. These targets make it relevant for cancer research.
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| ln Vitro |
At a dose of 0.7 μM, THZ-P1-2 (0.2-11.4 μM) suppresses PI-4, 5-P2 of PI5P4Kα and PI5P4Kγ by around 75%, and PI5P4Kβ by roughly 50% [1]. With IC50 values in the low micromolar range, -P1-2 (10 nM-100 μM; 72 hours) has regulated antiproliferative action in all six AML/ALL cell lines [1].
In vitro, THZ-P1-2 inhibits PI5P4Kα kinase activity with an IC50 of 190 nM. It covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. The compound disrupts autophagy by impairing autophagosome clearance and increasing TFEB nuclear localization. It induces cell death and mitochondrial damage and shows anticancer activity in leukemia cell lines. These in vitro activities support its use in cancer and autophagy research. |
| ln Vivo |
In vivo, THZ-P1-2 has potential applications in the treatment of leukemias based on its in vitro anticancer activity. By disrupting autophagy and mitochondrial homeostasis, it induces cell death in cancer cells. However, detailed in vivo efficacy data are limited. Further studies are needed to evaluate its therapeutic potential in animal models of leukemia and other cancers. The compound is currently used primarily as a research tool.
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| Enzyme Assay |
In vitro enzyme assays for THZ-P1-2 involve measuring PI5P4K kinase activity using purified enzymes (PI5P4Kα, β, γ). The compound is incubated with each kinase at concentrations ranging from 0.1-1000 nM, and kinase activity is measured using radiolabeled ATP or fluorescent substrates. IC50 values are determined. Covalent binding to cysteine residues is confirmed by mass spectrometry or Western blot. All assays include appropriate controls and reference compounds.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: THP1, SEMK2, OCI/AML-2, HL60, SKM1, NOMO1 Cell Tested Concentrations: 10-100000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Shown in all six AML/ALL cell lines Exhibits anti-proliferative activity with IC50 values ranging from 0.87 to 3.95μM. In vitro cell-based assays for THZ-P1-2 are conducted using leukemia cell lines or other cancer cell lines. Cells are treated with compound concentrations ranging from 0.1-1000 nM for 24-72 hours. Autophagy is assessed by measuring LC3-II conversion and autophagosome formation. TFEB nuclear localization is assessed by immunofluorescence. Cell viability is assessed using MTT assays. Mitochondrial damage is evaluated using JC-1 staining or Seahorse analysis. Apoptosis is evaluated by annexin V/PI staining. Experiments include vehicle controls and positive controls. |
| Animal Protocol |
In vivo animal studies with THZ-P1-2 are conducted in mouse xenograft models of leukemia. The compound is administered via intraperitoneal or intravenous injection at doses ranging from 1-50 mg/kg. Tumor growth is measured by caliper measurements. Autophagy and mitochondrial markers are assessed in tumor tissue. Pharmacokinetic studies assess compound exposure. Each group consists of 6-10 animals with vehicle-treated controls. Further studies are needed for comprehensive characterization.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of THZ-P1-2 have not been extensively characterized. As a small-molecule kinase inhibitor, it is expected to have moderate oral bioavailability and reasonable tissue distribution. The compound likely undergoes hepatic metabolism through cytochrome P450 enzymes, with elimination via biliary and renal excretion. Detailed PK parameters such as half-life, Cmax, and AUC require further investigation in preclinical species.
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| Toxicity/Toxicokinetics |
Toxicological data for THZ-P1-2 are limited, as the compound is a research tool. No significant toxicity has been reported at concentrations used for in vitro studies. The compound is a covalent inhibitor and may have off-target effects that require careful evaluation. Comprehensive toxicological profiling has not been conducted. As with all research chemicals, appropriate safety precautions should be taken during handling, and the compound should be used only for research purposes.
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| References | |
| Additional Infomation |
THZ-P1-2 is a first-in-class, selective PI5P4K inhibitor that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. It inhibits PI5P4Kα with an IC50 of 190 nM. The compound disrupts autophagy, impairs autophagosome clearance, increases TFEB nuclear localization, and induces mitochondrial damage and cell death. It shows anticancer activity in leukemia cell lines. Used in research on cancer and autophagy. Not approved for clinical use.
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| Molecular Formula |
C31H29N7O2
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|---|---|
| Molecular Weight |
531.607665777206
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| Exact Mass |
531.238
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| CAS # |
2058075-45-7
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| PubChem CID |
134451950
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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 |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
40
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| Complexity |
859
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=CC(=CC=1)NC(/C=C/CN(C)C)=O)NC1=CC=CC(=C1)NC1=CC(C2=CNC3C=CC=CC2=3)=NC=N1
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| InChi Key |
MJJJRRMQCUUKEO-IZZDOVSWSA-N
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| InChi Code |
InChI=1S/C31H29N7O2/c1-38(2)16-6-11-30(39)36-22-14-12-21(13-15-22)31(40)37-24-8-5-7-23(17-24)35-29-18-28(33-20-34-29)26-19-32-27-10-4-3-9-25(26)27/h3-15,17-20,32H,16H2,1-2H3,(H,36,39)(H,37,40)(H,33,34,35)/b11-6+
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| Chemical Name |
4-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[3-[[6-(1H-indol-3-yl)pyrimidin-4-yl]amino]phenyl]benzamide
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| Synonyms |
THZP12; THZ P1 2
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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 requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~100 mg/mL (~188.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 25 mg/mL (47.03 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 sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 250.0 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: ≥ 2.5 mg/mL (4.70 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 25.0 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: ≥ 2.5 mg/mL (4.70 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 | 1.8811 mL | 9.4054 mL | 18.8108 mL | |
| 5 mM | 0.3762 mL | 1.8811 mL | 3.7622 mL | |
| 10 mM | 0.1881 mL | 0.9405 mL | 1.8811 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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