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Purity: ≥98%
| Targets |
PF-06260933 targets MAP4K4 (also known as HGK), a member of the STE20 family of serine/threonine kinases involved in various cellular processes including cytoskeletal organization, cell migration, and inflammatory signaling. It also inhibits the closely related kinases MINK and TNIK. MAP4K4 is a key regulator of the JNK signaling pathway.
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| ln Vitro |
In vitro activity: PF-06260933 is a highly selective small-molecule inhibitor of MAP4K4 with IC50 values of 3.7 and 160 nM for cell-freel assay (kinase) and cell assay, respectively. It also inhibits MINK and TNIK with IC50 values of 8 and 13 nM, respectively. PF-06260933 has been reported to improve fasting hyperglycemia in mice. Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, PF-6260933.
Kinase Assay: Aortas were lysed in 1% NP-40, 50 mM Tris pH 7.4, 150 mM NaCl, 50 mM EDTA with 1 × HALT protease and phosphatase inhibitors (Thermo Scientific) and immunoprecipitated with Bethyl MAP4K4 antibodies (503 A; 1 μg) or normal rabbit IgG (Cell Signaling 2729; 1 μg). Myelin basic protein (MBP) (1 μg) and 10 μCi of [γ-32P]ATP were added to the immunoprecipitates and incubated for 30 min at 30 °C in kinase buffer (20 mM HEPES, 10 nM MgCl2, 1 mM dithiothreitol (DTT) and protease and phosphatase inhibitor cocktail). Samples were separated by 12% SDS–polyacrylamide gel electrophoresis and visualized by autoradiography. Cell Assay: HUVECs are maintained in EGM2 media at 37°C and 5% CO2. HUVECs or peritoneal macrophages are treated with vehicle or PF-06260933 in vitroto determine whether pharmacological inhibition of MAP4K4 alteres MAPK signalling in response to TNF-α In vitro, PF-06260933 shows potent inhibition of MAP4K4 with an IC50 of 3.7 nM in cell-free kinase assays. It also inhibits MINK and TNIK with IC50 values of 8 and 13 nM, respectively. In cell-based assays, it shows an IC50 of 160 nM. Detailed cellular activity data are not provided. |
| ln Vivo |
At 6–8 weeks of age, male flox/flox and flox/flox/cre+ littermates were injected with 1 mg tamoxifen per day in corn oil for 5 days. At 5–6 weeks of age (KD mice) or 2 weeks after tamoxifen injection (flox mice), the mice were fed chow or WD (0.2% cholesterol, TD 88137, Harlan Laboratories) for 16 weeks. Compound PF-06260933 (10 mg kg−1, dissolved in dH2O) was orally administered to 8–10-week-old male ApoE−/− mice twice daily for 6 weeks. Ldlr−/− male mice (B6.129S7-Ldlrtm1Her/J, Jackson Laboratories, 8–10 weeks old) were placed on HFD (1.25% cholesterol, TD96121, Harlan Laboratories) for 10 weeks before drug administration. Compound PF-06260933 was administered to male 8–10-week-old Ldlr−/− mice as above for 10 weeks. Oral administration of water was used as vehicle control in all studies. Mice were euthanized by CO2 inhalation followed by bilateral pneumothorax. No statistical methods were used to predict sample size, no randomization was performed and the investigations were not blinded during the knockout animal analyses, but were blinded during the drug treatment analyses.
In vivo activity data for PF-06260933 2HCl are not detailed in the available references. As a selective MAP4K4 inhibitor, it would be expected to have effects on JNK signaling, inflammation, and potentially tumor growth in preclinical models. Further studies would be needed to characterize its in vivo efficacy. |
| Enzyme Assay |
MAP4K4 kinase inhibitory activity is determined using cell-free kinase assays with recombinant MAP4K4 enzyme, a peptide substrate, and ATP. Phosphorylation of the substrate is measured, and IC50 values are calculated from dose-response curves. Selectivity is assessed by profiling against a panel of kinases including MINK and TNIK.
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| Cell Assay |
Cellular assays for PF-06260933 use cell lines relevant to MAP4K4 biology. Cells are treated with varying concentrations of the compound, and inhibition of MAP4K4-mediated signaling (e.g., JNK phosphorylation) is assessed by Western blot. Cell viability and functional assays related to MAP4K4 function (e.g., cell migration) may also be performed.
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| Animal Protocol |
Dissolved in dH2O; 10 mg/kg; orally administered
6–8 weeks of age, male flox/flox and flox/flox/cre+ littermates In vivo animal studies for PF-06260933 would be conducted in mouse models of diseases where MAP4K4 plays a role, such as inflammation or cancer. The compound would be administered orally or intraperitoneally, and efficacy endpoints would depend on the disease model. Detailed protocols are not provided. |
| ADME/Pharmacokinetics |
PF-06260933 2HCl has the molecular formula C₁₆H₁₃ClN₄·2HCl with a molecular weight of 369.68. It is a highly selective MAP4K4 inhibitor. Detailed pharmacokinetic parameters such as half-life, bioavailability, and tissue distribution are not disclosed in the available references.
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| Toxicity/Toxicokinetics |
No specific toxicity data are detailed in the available references. As a MAP4K4 inhibitor, potential toxicities would depend on the role of MAP4K4 in normal physiology. The compound's selectivity profile suggests it may have a favorable safety margin, but preclinical toxicology studies would be required for clinical development.
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| References |
ACS Med Chem Lett.2015 Oct 6;6(11):1128-33;Nat Commun.2015 Dec 21;6:8995.
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| Additional Infomation |
PF-06260933 2HCl is a research compound not yet approved for clinical use. It is a highly selective small-molecule inhibitor of MAP4K4, with additional activity against MINK and TNIK. It serves as a valuable pharmacological tool for studying MAP4K4-mediated signaling pathways and their roles in inflammation, cell migration, and cancer.
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| Molecular Formula |
C16H15CL3N4
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| Molecular Weight |
369.67610001564
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| Exact Mass |
368.036
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| CAS # |
1883548-86-4
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| Related CAS # |
1883548-86-4 (2HCl);1811510-56-1;2118243-34-6 (HCl);
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| PubChem CID |
118701007
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
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| Complexity |
332
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC(=CC=1)C1C(N)=NC=C(C2C=NC(=CC=2)N)C=1.Cl.Cl
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| InChi Key |
VRQXEOPUAQLBQI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H13ClN4.2ClH/c17-13-4-1-10(2-5-13)14-7-12(9-21-16(14)19)11-3-6-15(18)20-8-11;;/h1-9H,(H2,18,20)(H2,19,21);2*1H
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| Chemical Name |
5-(6-aminopyridin-3-yl)-3-(4-chlorophenyl)pyridin-2-amine;dihydrochloride
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| Synonyms |
PF-06260933 2HCl; PF 06260933 2HCl; PF06260933 2HCl;PF-06260933 dihydrochloride; PF 06260933 dihydrochloride; PF06260933dihydrochloride
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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) |
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 | 2.7050 mL | 13.5252 mL | 27.0504 mL | |
| 5 mM | 0.5410 mL | 2.7050 mL | 5.4101 mL | |
| 10 mM | 0.2705 mL | 1.3525 mL | 2.7050 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.
Pharmacological MAP4K4 inhibition ameliorates atherosclerosis.Nat Commun.2015 Dec 21;6:8995. |
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(a) Effects of16 (PF-06260933 )on LPS-induced TNFα levels in C57-BL/6J mice). (b) Effects of16on glycemic control inob/obmice.ACS Med Chem Lett.2015 Oct 6;6(11):1128-33. |
Total and free plasma concentration of16(PF-06260933 )after PO dosing (10 mg/kg) to mice.ACS Med Chem Lett.2015 Oct 6;6(11):1128-33. |
Heat map obtained from an Invitrogen selectivity panel (% inhibition of kinases tested @1 μM).ACS Med Chem Lett.2015 Oct 6;6(11):1128-33. |
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ACS Med Chem Lett.2015 Oct 6;6(11):1128-33. |
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