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Purity: ≥98%
PF-AKT400 (AKT-0286; ZINC-111606147), designed based on a 3-aminopyrrolidine scaffold, is a novel, selective, potent, ATP-competitive Akt kinase inhibitor with antitumor activity. It has a 900-fold greater selectivity for PKBα (IC50=0.5 nM) than PKA (IC50=450 nM). Intense research is being done to create selective protein kinase B (PKB/Akt) inhibitors in order to create potential anticancer drugs.
| Targets |
PKBα (IC50 = 0.5 nM); PKA (IC50 = 450 nM)
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|---|---|
| ln Vitro |
PF-AKT400 (Compound 42) provides significantly enhanced selectivity for Akt relative to earlier leads such as spiroindoline 2. For phospho-S6 reduction (110 nM) and Akt hyperphosphorylation (216 nM), respectively, the free IC50 and EC50 values are estimated. These values were in good agreement with the cellular IC50 for PF-AKT400 in U87 cells measured by p-GSK-3α (310 nM)[2].
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| ln Vivo |
PF-AKT400 is subsequently evaluated for modulation of Akt in tumors and in multiple in vivo mouse models of antitumor efficacy. In a PC3 prostate carcinoma xenograft experiment, it was effective; at 100 mg/kg b.i.d. dosing for 10 days, 75% TGI was seen. At 150 mg/kg b.i.d. after 10 days, PF-AKT400 produces 60% TGI in a colorectal carcinoma (Colo205) xenograft study. The most intriguing finding is that 75 mg/kg b.i.d. (10 days) of PF-AKT400 in combination with Rapamycin (10 mg/kg, ip) results in 98% TGI in a separate PC3 prostate carcinoma xenograft study, compared to 56% TGI and 66% TGI with PF-AKT400 and Rapamycin as single agents. In the PC3 xenograft model, oral administration of 25, 75, and 100 mg/kg of PF-AKT400 (Compound 42) is carried out with blood and tumor sampling over time in order to define the in vivo potency of the compound. When treated at doses that produced significant tumor growth inhibition, immunoblot analysis of detergent-soluble extracts from PC3 tumors reveals a significant reduction of S6 phosphorylation and hyperphosphorylation of Akt. After oral administration of doses ranging from 25 to 100 mg/kg (Tmax=0.5 h), plasma drug concentrations quickly peak. At roughly 2-4 hours and 1 hour after PF-AKT400 administration, respectively, the peak PD responses of phospho-S6 and phospho-Akt are seen. A PK/PD model at doses ranging from no efficacy (25 mg/kg) to maximal efficacy (100 mg/kg) accurately describes the time-course of the PD marker response[2].
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| Enzyme Assay |
A fluorescence polarization IMAP type assay is used. A mixture of 60 L of reaction buffer (10 mM Tris-HCl, pH 7.5, 10 mM MgCl2, 0.1 mM EGTA, 0.01% Triton-X100, and 1 mM DTT) and 15 L of diluted PF-AKT400 (Compound 42) in DMSO is used. Then 5 μL of the compound/buffer mixture, 10 μL of a solution containing 4 μM ATP and 40 nM fluorescent-labeled Crosstide (Tamara-labeled GRPRTSSFAEG peptide), and 5 μL of Akt1 protein (lacking the pleckstrin homology (PH) domain, containing an Asp at position 473, and prephosphorylated at Thr 308) in reaction buffer are combined. After a 90 min incubation, IMAP beads are added and plates are read (lamp filter, 544 nm; emission filter, 615 nm). The same process can be used on the entire length of Akt1 to produce results that are comparable. The geometric mean of at least n=2 measurements serves as the basis for all IC50 values[2].
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| Animal Protocol |
Mice: Male SCID/Beige mice bearing subcutaneous PC3 prostate carcinoma xenografts are used in studies to describe the PK/PD relationship for PF-AKT400. Three mice per dose group are given PF-AKT400 orally once tumors have grown to a size of approximately 300mm3. The drug is formulated in a 0.5% methylcellulose vehicle. The levels of phospho S6 reduction and phospho Akt induction are assessed by immunoblot after the preparation of tumor lysates and the periodic collection of plasma and tumors.
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| References |
| Molecular Formula |
C20H22N6OF2
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|---|---|
| Molecular Weight |
400.42508
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| Exact Mass |
400.18232
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| Elemental Analysis |
C, 59.99; H, 5.54; F, 9.49; N, 20.99; O, 4.00
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| CAS # |
1004990-28-6
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| Related CAS # |
1004990-28-6
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| Appearance |
Solid powder
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| SMILES |
CCC1=CNC2=C1C(=NC=N2)N3CC[C@@](C3)(CNC(=O)C4=C(C=C(C=C4)F)F)N
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| InChi Key |
MOZRQQTUYAYCQT-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C20H22F2N6O/c1-2-12-8-24-17-16(12)18(27-11-26-17)28-6-5-20(23,10-28)9-25-19(29)14-4-3-13(21)7-15(14)22/h3-4,7-8,11H,2,5-6,9-10,23H2,1H3,(H,25,29)(H,24,26,27)/t20-/m0/s1
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| Chemical Name |
N-[[(3S)-3-amino-1-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]methyl]-2,4-difluorobenzamide
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| Synonyms |
PF-AKT400; AKT0286; ZINC-111606147; Lig-1; Lig 1; PF AKT400; AKT-0286; AKT 0286; ZINC 111606147; ZINC111606147; PFAKT400; AKT protein kinase inhibitor; PF AKT400
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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: ≥100 mg/mL (~249.7 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.24 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 (6.24 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 (6.24 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 | 2.4973 mL | 12.4866 mL | 24.9732 mL | |
| 5 mM | 0.4995 mL | 2.4973 mL | 4.9946 mL | |
| 10 mM | 0.2497 mL | 1.2487 mL | 2.4973 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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