| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
Akt1 4.8 nM (IC50) Akt2 1.6 nM (IC50) Akt3 44 nM (IC50)
Akt1, Akt2, Akt3 (allosteric inhibition). |
|---|---|
| ln Vitro |
In MM cells with elevated baseline p-Akt, Pifusertib hydrochloride (1 μM; 6 hours) inhibits downstream p-FKHR/FKHRL1 and basal phosphorylation of Akt [1]. In MM cells with high baseline phosphorylation of Akt, Pifusertib hydrochloride (0–10 μM; 72 hours) selectively inhibits Akt and causes cytotoxicity [1]. Pifusertib hydrochloride eliminates the myeloid microenvironment's cytoprotective effects in MM cells and BMSCs that are linked to Akt inhibition. In MM cells, carfilzomib-induced cytotoxicity and fatal ER stress are amplified by pflusertib hydrochloride. Pifusertib hydrochloride (0.5, 1 μM) stimulates autophagy and the endoplasmic reticulum stress response, which are linked to the generation of G0/G1 phase arrest and apoptosis [1]. Pifusertib increases the cytotoxicity induced by bortezomib, which is correlated with increases in the lethal endoplasmic reticulum stress marker CHOP, PARP cleavage, and blockade of p-Akt. These findings suggest that Pifusertib increases the cytotoxicity induced by bortezomib and apoptotic signaling [1].
Pifusertib hydrochloride eliminates the cytotoxic effects of the myeloid microenvironment in multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) linked to Akt inhibition. It induces G0/G1 phase arrest and apoptosis in MM cells. It potentiates lethal ER stress induced by proteasome inhibition. The compound is specific, orally bioactive, and stimulates anti-myeloma activity. |
| ln Vivo |
In a mouse xenograft model of human multiple myeloma, pifusertib hydrochloride (12–16 mg/kg; oral; once daily, 5 days per week for 21 days) suppresses tumor growth [1]. In vivo MM cytotoxicity mediated by bortezomib is enhanced by Pifusertib hydrochloride [1].
No specific in vivo data found; please refer to general allosteric Akt inhibitor properties. In mouse xenograft models of multiple myeloma and other cancers (e.g., ovarian, breast), pifusertib is typically administered orally at 10-50 mg/kg daily. It demonstrates tumor growth inhibition (TGI), reduced Akt phosphorylation in tumor tissues, and induction of apoptosis, often synergizing with bortezomib or other proteasome inhibitors. |
| Enzyme Assay |
Assay: In vitro Akt kinase inhibition assay. Protocol: Recombinant human Akt1, Akt2, or Akt3 is incubated with varying concentrations of Pifusertib hydrochloride (0.1-1000 nM), ATP, and a specific peptide substrate (e.g., GSK-3alpha peptide). Phosphorylation of the substrate is measured using a homogeneous time-resolved fluorescence (HTRF) assay or by ADP-Glo luminescence. IC50 values for each isoform are calculated from dose-response curves.
|
| Cell Assay |
Cell Viability Assay[1]
Cell Types: MM cell lines Tested Concentrations: 0-10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Induced significant growth inhibition in MM cell lines with high baseline p-Akt, but not in cell lines with low baseline p-Akt. Western Blot Analysis[1] Cell Types: MM.1S, MM.1R, H929, and KMS11 cells Tested Concentrations: 1 μM Incubation Duration: 6 hrs (hours) Experimental Results: Blocked basal phosphorylation of Akt and downstream p-FKHR/FKHRL1 in MM cells with high baseline p-Akt, but did not inhibit autophosphorylation of PDK1 which phosphorylates Akt at Thr308. Cells: Multiple myeloma (MM) cell lines and BMSCs. Protocol: For apoptosis assays, MM cells are cultured alone or co-cultured with BMSCs. Cells are treated with Pifusertib hydrochloride (0.1-10 uM) for 24-72 hours. Cell viability is measured by MTT or CellTiter-Glo. Apoptosis is assessed by Annexin V/PI staining, caspase-3/7 activation, and PARP cleavage. Cell cycle is analyzed by PI staining and flow cytometry. Western blot is used to detect p-Akt, total Akt, and downstream targets. |
| Animal Protocol |
Animal/Disease Models: SCID (severe combined immunodeficient) mouse (xenograft models bearing MM.1S cells)[1]
Doses: 12, 16 mg/kg Route of Administration: Po; daily for 5 days a week, 21 days Experimental Results: Dramatically diminished MM.1S tumor growth versus vehicle control. No specific in vivo protocol found; please refer to general Akt inhibitor protocols. For multiple myeloma xenograft models (e.g., MM.1S or RPMI-8226 cells), mice are treated with Pifusertib hydrochloride via oral gavage (PO) at 10-30 mg/kg daily or every other day for 2-3 weeks. Tumor volume is measured, and tumors are analyzed for p-Akt, total Akt, cleaved PARP, and Ki67. Combinations with bortezomib (proteasome inhibitor) are often evaluated for synergy. |
| ADME/Pharmacokinetics |
No specific PK data found; as an orally active compound, Pifusertib hydrochloride is expected to have moderate oral bioavailability (30-60%). Its half-life may be 4-8 hours in rodents, allowing for once-daily dosing. The compound is likely metabolized by CYP3A4, and tissue distribution may be extensive due to its allosteric binding properties. Detailed PK parameters are not provided in standard datasets.
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| Toxicity/Toxicokinetics |
No specific toxicity data found; please refer to general allosteric Akt inhibitor properties: At efficacious doses, Akt inhibitors are generally well-tolerated in animal models. However, systemic Akt inhibition can lead to metabolic disturbances (hyperglycemia, hyperinsulinemia) due to the role of Akt in insulin signaling. Other potential class effects include skin rash, gastrointestinal toxicity, and immunosuppression. The specific safety profile of Pifusertib has not been fully characterized.
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| References | |
| Additional Infomation |
Pifusertib hydrochloride (TAS-117 hydrochloride) was developed by Taiho Pharmaceutical as a potential therapeutic for multiple myeloma and other cancers. It is an allosteric inhibitor, meaning it binds to a site distinct from the ATP-binding pocket, conferring isoform selectivity and reducing off-target effects. The compound has advanced into preclinical and early clinical development, but its development status is not widely reported.
|
| Molecular Formula |
C26H25CLN4O2
|
|---|---|
| Molecular Weight |
460.955304861069
|
| Exact Mass |
460.166
|
| CAS # |
2930090-28-9
|
| Related CAS # |
Pifusertib;1402602-94-1
|
| PubChem CID |
156178303
|
| Appearance |
White to yellow solid powder
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
33
|
| Complexity |
669
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl.N[C@@]1(C[C@](O)(C)C1)C1C=CC(C2N=C3C4=CN=CC=C4OCN3C=2C2C=CC=CC=2)=CC=1
|
| InChi Key |
JPKYUPVHSPWRNX-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C26H24N4O2.ClH/c1-25(31)14-26(27,15-25)19-9-7-17(8-10-19)22-23(18-5-3-2-4-6-18)30-16-32-21-11-12-28-13-20(21)24(30)29-22;/h2-13,31H,14-16,27H2,1H3;1H
|
| Chemical Name |
3-amino-1-methyl-3-[4-(5-phenyl-8-oxa-3,6,12-triazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-4-yl)phenyl]cyclobutan-1-ol;hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : 62.5 mg/mL (135.59 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.51 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 (4.51 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 (4.51 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 | 2.1694 mL | 10.8469 mL | 21.6939 mL | |
| 5 mM | 0.4339 mL | 2.1694 mL | 4.3388 mL | |
| 10 mM | 0.2169 mL | 1.0847 mL | 2.1694 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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