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Purity: ≥98%
AT13148 is a novel, potent, orally bioavailable, ATP-competitive, multi-AGC kinase inhibitor with potential anticancer activity. Its respective IC50 values for Akt1/2/3, p70S6K, PKA, and ROCKI/II are 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM. n cancer cells with clinically significant genetic flaws, AT13148 significantly inhibited the phosphorylation of AKT, p70S6K, PKA, ROCK, and SGK substrates and, in a concentration- and time-dependent manner, induced apoptosis in vitro and in vivo. In addition, AT13148 has been revealed to inhibit proliferation with GI50 values of 1.54μM, 1.59μM, 1.82μM, 2.65μM and 3.77μM in MES-SA, BT474, HCT-116, A549 and SK-OV-3 cell lines, respectively.
| Targets |
Akt1 (IC50 = 38 nM); p70S6K (IC50 = 8 nM); Akt3 (IC50 = 50 nM); Akt2 (IC50 = 402 nM); PKA (IC50 = 3 nM); ROCKII (IC50 = 4 nM); ROCKI (IC50 = 6 nM); SGK3 (IC50 = 63 nM); RSK1 (IC50 = 85 nM); CHK2 (IC50 = 860 nM); Aurora B (IC50 = 1840 nM)
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| ln Vitro |
AT13148, as a multi-AGC kinase inhibitor, potently inhibits proliferation with GI50 values of 1.5 to 3.8 μM across a selected panel of cancer cell lines with deregulation of PI3K-AKT-mTOR or RAS-RAF pathways. Additionally, AT13148 inhibits p70S6K and AKT signaling in PTEN-deficient MES-SA cells.[1]
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| ln Vivo |
AT13148 (50 mg/kg p.o.) exhibits strong antitumor effects in human tumor xenografts by significantly inhibiting the activity of both AKT and p70S6K AGC kinases. [1]
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| Enzyme Assay |
AT13148 is assayed against 40 kinases and the percentage inhibition at 10 μM of AT13148 is determined. Using ATP concentrations equivalent to each enzyme's Km, the individual IC50 values for a few kinases are determined.
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| Cell Assay |
Cells are seeded onto 96-well micro-plates at a density of 1×104 cells per well. Following therapy, MTT solution (0.5 mg/mL) is added for 2–3 hours. The optical density (OD), which is measured at 570 nm using a microplate reader, is obtained after the MTT-purple formazan productions are dissolved in 0.1 N hydrochloric acid.
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| Animal Protocol |
For pharmacokinetic analysis, male athymic BALB/c mice are obtained from Harlan. AT13148 is administered at 5 mg/kg i.v. or p.o. and is made up of 10% DMSO, 1% Tween-20, and 89% saline. At 1, 2, 4, 6, 8, 16, 24, and 72 hours after administration, cardiac punctures are used to obtain duplicate samples of whole blood that has been heparinized. In preparation for analysis, plasma and tissues (including liver, kidney, spleen, and muscle) are frozen at -20°C. Using acetonitrile with an internal standard to extract it from plasma and tissues, AT13148 is then quantified using the liquid chromatography tandem mass spectrometry (LC-MS/MS) technique and the appropriate standard curves. In order to calculate pharmacokinetic parameters, WinNonLin software version 5.2 is used.
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| References |
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| Additional Infomation |
Multi-AGC Kinase Inhibitor AT13148 is an orally available, small molecule inhibitor of AGC group kinases, with potential antineoplastic activity. AT13148 inhibits, in an ATP-competitive manner, the enzymatic activity of two AGC kinases, protein kinase B (PKB or AKT) and p70S6K which play key roles in the PI3K/PKB/mTOR signaling pathway. Blockade of this pathway leads to an inhibition of cell growth and the induction of apoptosis in susceptible tumor cells. PI3K/PKB/mTOR pathway is dysregulated in greater than 50% of tumors, and is often correlated with resistance and increased tumor survival. AGC group kinases are serine/threonine kinases that are regulated by secondary messengers such as cyclic AMP and lipids.
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| Molecular Formula |
C17H16CLN3O
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|---|---|
| Molecular Weight |
313.78
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| Exact Mass |
313.78
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| Elemental Analysis |
C, 65.07; H, 5.14; Cl, 11.30; N, 13.39; O, 5.10
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| CAS # |
1056901-62-2
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| Related CAS # |
1056901-62-2; 1056901-67-7 (R-isomer);857532-13-9 (racemic);
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| PubChem CID |
24905401
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| Appearance |
white solid powder
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| LogP |
5.229
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
354
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1=CC=C([C@](C2=CC=C(C3=CNN=C3)C=C2)(O)CN)C=C1
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| InChi Key |
IIRWNGPLJQXWFJ-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C17H16ClN3O/c18-16-7-5-15(6-8-16)17(22,11-19)14-3-1-12(2-4-14)13-9-20-21-10-13/h1-10,22H,11,19H2,(H,20,21)/t17-/m0/s1
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| Chemical Name |
(1S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)phenyl]ethanol
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| Synonyms |
AT-13148; AT 13148; AT13148; AT13148 hydrochloride; AT13148 HCl
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.97 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.97 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.97 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 | 3.1869 mL | 15.9347 mL | 31.8695 mL | |
| 5 mM | 0.6374 mL | 3.1869 mL | 6.3739 mL | |
| 10 mM | 0.3187 mL | 1.5935 mL | 3.1869 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 | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01585701 | Completed | Biological: AT13148 | Cancer Research UK | Advanced Solid Tumours | May 2012 | Phase 1 |
The effect of AT13148 exposure on AGC kinase biomarker expression. |
Pharmacodynamic biomarker and antitumor activity of AT13148 in human tumor xenografts. Clin Cancer Res. 2012, 18(14), 3912-3923. |
Comparison of the effects of 6-hour treatment of AT13148 versus CCT128930 on gene and protein expression in U87MG human glioblastoma cells |
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