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| Targets |
Akt1:3.5 nM (IC50); Akt2:42 nM (IC50)
Akt Inhibitor 17 targets Akt1 and Akt2, two isoforms of the serine/threonine protein kinase Akt (also known as protein kinase B, PKB). Akt is a key downstream effector of the PI3K signaling pathway and regulates various cellular processes, including cell survival, proliferation, metabolism, and angiogenesis. The compound is an allosteric inhibitor, meaning it binds to a site distinct from the active site, inducing a conformational change that inhibits kinase activity. It has potent and balanced activity against Akt1 (IC50 = 3.5 nM) and Akt2 (IC50 = 42 nM). |
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| ln Vitro |
In line with the allosteric method of inhibition, Akt1/Akt2-IN-1 (Compound 17) exhibits PH-domain dependence for Akt inhibition, a high degree of selectivity (>50 μM vs. PKA, PKC, SGK) for Akt1/2 over Akt3 (IC50=1900 nM), and a dependence on the PH-domain for Akt inhibition. Human P-glycoprotein is a substrate of Akt1/Akt2-IN-1, which exhibits modest activity in a hERG binding experiment (IC50=5610 nM) [1].
In vitro, Akt Inhibitor 17 is a potent allosteric inhibitor of Akt1 (IC50 = 3.5 nM) and Akt2 (IC50 = 42 nM). It shows potent and balanced activity against these two isoforms. The compound has improved cell potency and physical properties compared to earlier inhibitors. In cell-based assays, Akt Inhibitor 17 can inhibit Akt phosphorylation and downstream signaling, leading to reduced cell proliferation and increased apoptosis in cancer cell lines. |
| ln Vivo |
Compound 17, Akt1/Akt2-IN-1, exhibits good tolerance at doses that result in significant in vivo inhibition of Akt1 and 2. When taken as monotherapy, Akt1/Akt2-IN-1 has also been demonstrated to reduce the growth of A2780 tumors in vivo. Akt1/Akt2-IN-1 is effective in a tumor xenograft model and exhibits strong inhibitory activity against Akt1 and 2 in vivo in a mouse lung. With a half-life of 3.8 hours and a low clearance of 4.6 mL/min/kg, Akt1/Akt2-IN-1 has excellent pharmacokinetics in rats. Since Akt1/Akt2-IN-1 has better cell potency, physical characteristics, and rodent pharmacokinetics, mice are used to evaluate tolerance and Akt inhibition. Administering Akt1/Akt2-IN-1 to mice on an acute dosing schedule (IP dosing of 50 mg/kg at times 0, 3, and 8 h) results in high levels of Akt inhibition in the mouse lung[1]. The mice also respond well to this treatment.
In vivo, Akt Inhibitor 17 shows good pharmacokinetics in rats with a low clearance of 4.6 mL/min/kg and a half-life of 3.8 hours. Due to the improved cell potency, physical properties, and rodent pharmacokinetics, tolerability and Akt inhibition are assessed in mice. The compound has anticancer activity. It has been studied in preclinical models to evaluate its efficacy and safety, but specific in vivo efficacy data are limited in the available literature. |
| Enzyme Assay |
Non-cellular in vitro assays for Akt Inhibitor 17 involve measuring its inhibition of Akt kinase activity. A typical protocol uses purified recombinant human Akt1 or Akt2 enzyme. The enzyme is incubated with ATP and a peptide substrate in the presence of varying concentrations of the inhibitor. The phosphorylation of the substrate is measured using a luminescent or fluorescence-based detection method, such as the ADP-Glo™ Kinase Assay or by using radiolabeled [γ-³²P]ATP. The IC50 is determined from the concentration-response curve.
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| Cell Assay |
Cellular assays for Akt Inhibitor 17 are performed using cancer cell lines that express Akt1 and Akt2, such as PC-3 or MCF-7 cells. Cells are treated with the inhibitor at various concentrations for 2-24 hours. Akt phosphorylation (at Ser473 and Thr308) and the phosphorylation of downstream targets such as GSK3β, PRAS40, and FOXO are assessed by Western blotting using phospho-specific antibodies. Cell proliferation is measured using an MTT or CellTiter-Glo assay. Apoptosis is assessed by measuring caspase-3/7 activity or by flow cytometry using annexin V staining.
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| Animal Protocol |
In vivo animal studies for Akt Inhibitor 17 are conducted in mouse xenograft models of cancer. Mice bearing tumors are administered the inhibitor orally or intraperitoneally at doses such as 10-50 mg/kg. Tumor volume is measured over time to assess antitumor efficacy. Body weight and clinical signs are monitored to assess tolerability. At the end of the study, tumor tissues are collected for analysis of Akt phosphorylation and downstream signaling. Pharmacokinetic parameters are also assessed in these studies.
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| ADME/Pharmacokinetics |
Akt Inhibitor 17 shows good pharmacokinetics in rats with a low clearance of 4.6 mL/min/kg and a half-life of 3.8 hours. It has improved physical properties compared to earlier inhibitors. For in vivo studies, it can be formulated in standard vehicles for oral or intraperitoneal administration. The compound is stored as a powder at -20°C. Specific molecular weight and formula are not detailed in the available literature.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for Akt Inhibitor 17 have not been extensively reported. As a research chemical, it is not intended for human use and is strictly for preclinical research purposes. Standard safety precautions should be followed when handling Akt Inhibitor 17, including the use of personal protective equipment. No specific toxicity data, such as LD50 values, are available in the provided literature.
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| References | |
| Additional Infomation |
Akt Inhibitor 17 (Akt1 and Akt2-IN-1, Compound 17) is a novel and potent allosteric inhibitor of Akt1 (IC50 = 3.5 nM) and Akt2 (IC50 = 42 nM). It shows potent and balanced activity against these two isoforms. The compound has anticancer activity. It shows good pharmacokinetics in rats with a low clearance of 4.6 mL/min/kg and a half-life of 3.8 hours. Tolerability and Akt inhibition are assessed in mice. Akt Inhibitor 17 is not a clinically approved drug and has not entered clinical trials. Its primary application is in research on the PI3K/Akt signaling pathway and anticancer drug development.
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| Molecular Formula |
C33H29N7O
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|---|---|
| Molecular Weight |
539.64
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| Exact Mass |
539.243
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| CAS # |
893422-47-4
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| PubChem CID |
11656753
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.666
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| LogP |
3.59
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
41
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| Complexity |
892
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2C(=NC(=C(C3C=CC=CC=3)C=2)C2C=CC(CN3CCC(C4NC(C5C=CC=CN=5)=NN=4)CC3)=CC=2)C=CN1
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| InChi Key |
BTUWHHFNOHVCMQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H29N7O/c41-33-27-20-26(23-6-2-1-3-7-23)30(36-28(27)13-17-35-33)24-11-9-22(10-12-24)21-40-18-14-25(15-19-40)31-37-32(39-38-31)29-8-4-5-16-34-29/h1-13,16-17,20,25H,14-15,18-19,21H2,(H,35,41)(H,37,38,39)
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| Chemical Name |
3-phenyl-2-[4-[[4-(3-pyridin-2-yl-1H-1,2,4-triazol-5-yl)piperidin-1-yl]methyl]phenyl]-6H-1,6-naphthyridin-5-one
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| Synonyms |
Akt Inhibitor 17 Akti 2008 Akti_2008
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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 : ≥ 35 mg/mL (~64.86 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 | 1.8531 mL | 9.2654 mL | 18.5309 mL | |
| 5 mM | 0.3706 mL | 1.8531 mL | 3.7062 mL | |
| 10 mM | 0.1853 mL | 0.9265 mL | 1.8531 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03733119 | TERMINATEDWITH RESULTS | Drug: Akt/ERK Inhibitor ONC201 Dietary Supplement: Methionine-Restricted Diet |
Triple Negative Breast Cancer | University of Wisconsin, Madison | 2018-11-13 | Phase 2 |
| NCT01240941 | WITHDRAWN | Drug: MK-2206 Drug: Exemestane Drug: Goserelin |
Metastatic Breast Cancer | Vanderbilt-Ingram Cancer Center | 2011-02 | Phase 2 |
| NCT01705340 | TERMINATED | Drug: Akt inhibitor MK2206 Biological: trastuzumab Drug: lapatinib ditosylate Other: laboratory biomarker analysis |
Adenocarcinoma of the Gastroesophageal Junction HER2-positive Breast Cancer Male Breast Cancer Recurrent Breast Cancer |
National Cancer Institute (NCI) | 2012-09 | Phase 1 |
| NCT01776008 | TERMINATEDWITH RESULTS | Drug: Akt Inhibitor MK2206 Drug: Anastrozole Drug: Goserelin Acetate |
Estrogen Receptor Positive HER2/Neu Negative Recurrent Breast Carcinoma Stage IIA Breast Cancer |
National Cancer Institute (NCI) | 2013-01 | Phase 2 |
| NCT04690725 | UNKNOWN STATUS | Drug: TQB3525 | Efficacy, Self Safety Issues |
Peking University People's Hospital | 2020-10-01 | Phase 1 Phase 2 |
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