| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Targets |
The compound specifically targets PI3Kalpha (Class IA PI3K), the most frequently mutated kinase in human cancers, particularly in breast, endometrial, and colorectal cancers. It shows selectivity for PI3Kalpha over PI3Kdelta (Ki < 0.018 nM vs. < 0.28 nM). By inhibiting PI3Kalpha, PF-06843195 blocks the conversion of PIP2 to PIP3, thereby preventing the activation of AKT and downstream signaling (mTOR, S6K, 4E-BP1) involved in cell growth, proliferation, and survival.
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| ln Vitro |
Breast cancer cell lines MCF7 and T47D are inhibited from proliferating by PF-06843195, with IC50 values of 62 nM and 32 nM, respectively[1]. In MCF7 and T47D cells, PF-06843195 suppresses pAKT (T308) with IC50 values of 7.8 nM and 8.7 nM, respectively [1].
PF-06843195 exhibits potent PI3Kalpha inhibition with a Ki of less than 0.018 nM in biochemical kinase assays, indicating extremely high binding affinity. In Rat1 fibroblasts, the compound shows an IC50 of 18 nM. It demonstrates significant inhibitory activity against the PI3K/mTOR signaling pathway and has a durable anti-tumor effect in pre-clinical models. The selectivity over PI3Kdelta (Ki < 0.28 nM) is also high, though not absolute. |
| ln Vivo |
In rats, PF-06843195 can be promptly and quantitatively transformed from PF-06862309 [1]. PF-06843195 displays oral bioavailability (25% in rat) following oral dosing (rat 10 mg/kg) [1]. PF-06843195 has an intermediate half-life (rat 3.6) due to high plasma clearance (30 mL/min/kg) and large volume of distribution (3.0 L/kg) following intravenous treatment (rat 2 mg/kg) hours)[1].
Specific in vivo efficacy data for PF-06843195 are not detailed, but the compound is described as having a durable anti-tumor effect. As a selective PI3Kalpha inhibitor, it would be evaluated in mouse xenograft models of PI3Kalpha-mutant cancers such as breast cancer (MCF-7 with PIK3CA mutations), endometrial cancer, or colorectal cancer. A typical protocol would involve oral administration daily at doses of 10-50 mg/kg and measurement of tumor growth inhibition and AKT phosphorylation levels in tumor tissue. |
| Enzyme Assay |
The biochemical PI3Kalpha kinase assay is performed using a homogeneous time-resolved fluorescence (HTRF) or luminescent ADP-Glo assay. Purified recombinant human PI3Kalpha (p110alpha/p85alpha complex) is incubated with phosphatidylinositol-4,5-bisphosphate (PIP2) substrate and ATP in the presence of varying concentrations of PF-06843195 in reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Tween-20). After incubation at 30degC for 60 minutes, the amount of PIP3 produced is measured using a specific GRP1 PH domain-based detection reagent. The Ki is calculated from the dose-response curve using the Cheng-Prusoff equation.
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| Cell Assay |
A cellular PI3K pathway inhibition assay is performed in Rat1 fibroblasts or PI3Kalpha-dependent cancer cell lines (e.g., MCF-7, T47D). Cells are seeded in 6-well plates and starved in serum-free medium overnight. They are then treated with varying concentrations of PF-06843195 (1-1000 nM) for 1-2 hours, followed by stimulation with insulin (100 nM) or IGF-1 (50 ng/mL) to activate PI3K signaling. Cells are lysed, and the levels of phosphorylated AKT (pAKT S473 and T308), total AKT, phosphorylated S6 ribosomal protein (pS6), and total S6 are analyzed by Western blot to determine the IC50 for pathway inhibition. Cell viability is measured after 72-96 hours of treatment using CellTiter-Glo.
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| Animal Protocol |
Animal/Disease Models: Male Wistar Han rat[1]
Doses: 2 mg/kg (intravenous) and 10 mg/kg (po (oral gavage)) (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)(IV) or po (oral gavage) Experimental Results: T1/2 rats were 3.6 hrs (hrs (hours)). In vivo efficacy is evaluated in a mouse xenograft model of PI3Kalpha-mutant breast cancer. Female athymic nude mice are injected subcutaneously with MCF-7 (PIK3CA E545K mutant) cells in Matrigel. When tumors reach approximately 150-200 mm3, mice are randomized into treatment groups. PF-06843195 is administered via oral gavage daily at doses of 5, 15, or 45 mg/kg for 2-4 weeks. Tumor volume is measured by calipers twice weekly. On study termination, tumors are harvested for Western blot analysis of pAKT and pS6, and for immunohistochemistry of Ki-67 and cleaved caspase-3. Plasma samples are collected to determine exposure levels. |
| ADME/Pharmacokinetics |
PF-06843195 displays oral bioavailability (25% in rat) following oral dosing (rat 10 mg/kg). It has an intermediate half-life (3.6 hours in rat) due to high plasma clearance (30 mL/min/kg) and a large volume of distribution (3.0 L/kg) following intravenous treatment (rat 2 mg/kg). These PK properties are consistent with small-molecule inhibitors of PI3K (MW ~514.5) and support once-daily oral dosing. Key parameters include: Rat: T1/2 = 3.6 h, CL = 30 mL/min/kg, Vdss = 3.0 L/kg, F% (rat) = 25%.
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| Toxicity/Toxicokinetics |
Specific toxicological data for PF-06843195 are not detailed. As a PI3Kalpha inhibitor, class-related toxicities may include hyperglycemia (due to inhibition of insulin signaling), rash, diarrhea, and stomatitis, which are known side effects of PI3Kalpha inhibitors such as alpelisib. The selectivity for PI3Kalpha over PI3Kdelta may reduce hematological toxicities associated with PI3Kdelta inhibition (e.g., hepatotoxicity, colitis). Standard toxicological endpoints would be assessed in animal studies (e.g., blood glucose monitoring, histopathology of GI tract).
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| References | |
| Additional Infomation |
PF-06843195 is a research-grade chemical tool for studying PI3Kalpha biology. PI3Kalpha is one of the most frequently mutated oncogenes in human cancers, and selective PI3Kalpha inhibitors such as alpelisib are approved for the treatment of PIK3CA-mutant breast cancer. PF-06843195 allows researchers to investigate the specific role of PI3Kalpha in cancer cell growth and survival, and to explore combination therapies with other targeted agents or chemotherapies. As of the latest updates, the compound has not been approved for clinical use.
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| Molecular Formula |
C20H25F3N8O4
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|---|---|
| Molecular Weight |
498.4589
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| Exact Mass |
498.195
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| CAS # |
2067281-51-8
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| PubChem CID |
124193915
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| Appearance |
White to off-white solid powder
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| LogP |
0.4
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
701
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1=C(C2=C([H])N=C(N([H])[H])N=C2[H])N=C(N2C([H])([H])C([H])([H])OC([H])([H])C2([H])[H])N=C1N([H])[C@]1(C([H])([H])O[H])C([H])([H])N(C(=O)OC([H])([H])C([H])(F)F)C([H])([H])C1([H])[H]
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| InChi Key |
RTOREZYNLPQUKM-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C20H25F3N8O4/c21-13(22)9-35-19(33)31-2-1-20(10-31,11-32)29-16-14(23)15(12-7-25-17(24)26-8-12)27-18(28-16)30-3-5-34-6-4-30/h7-8,13,32H,1-6,9-11H2,(H2,24,25,26)(H,27,28,29)/t20-/m0/s1
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| Chemical Name |
2,2-difluoroethyl (3S)-3-[[6-(2-aminopyrimidin-5-yl)-5-fluoro-2-morpholin-4-ylpyrimidin-4-yl]amino]-3-(hydroxymethyl)pyrrolidine-1-carboxylate
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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 : ~62.5 mg/mL (~125.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.17 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 (4.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0062 mL | 10.0309 mL | 20.0618 mL | |
| 5 mM | 0.4012 mL | 2.0062 mL | 4.0124 mL | |
| 10 mM | 0.2006 mL | 1.0031 mL | 2.0062 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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