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Purity: ≥98%
PF-06263276 (PF6263276) is a novel, indazole-based, potent and selective pan-JAK inhibitor with anti- inflammatory and immunomodulatory effects. It inhibits JAK1/2/3 and TYK2 with IC50s of 2.2 nM, 23.1 nM, 59.9 nM and 29.7 nM, respectively. It is suitable for inhaled and topical delivery for the treatment of inflammatory diseases of the lungs and skin and was advanced into clinical studies. Janus kinases (JAKs) are a family of tyrosine kinases comprising four members (JAK1, -2, -3, and Tyk2). They play a critical role in both innate and adaptive immunity, since they function as key transducers in the signaling processes of many cytokine receptors.
PF-06263276 is a potent pan‑Janus kinase (JAK) inhibitor designed for inhaled or topical delivery to treat inflammatory diseases of the lungs (e.g., COPD) and skin (e.g., mild‑to‑moderate psoriasis). It binds to JAK2 in a type‑1.5 binding mode, as confirmed by X‑ray crystallography, and exhibits high enzymatic potency (JAK1 IC₅₀ = 0.8 nM, JAK2 IC₅₀ = 7.9 nM, JAK3 IC₅₀ = 16.7 nM, TYK2 IC₅₀ = 15.3 nM at 1 mM ATP). In human whole blood, PF‑06263276 blocks STAT phosphorylation induced by cytokines that signal through various JAK dimers, with free IC₅₀ values in the low nanomolar range. The compound has a long cellular duration of action (T₁/₂ = 9 h in PBMC wash‑out assays) and shows high selectivity over non‑JAK kinases. Owing to its very high systemic clearance (CLunbound > 48,000 mL/min/kg in rat) and minimal predicted oral absorption, PF‑06263276 is designed to achieve organ‑targeted efficacy with negligible systemic exposure. In mouse models, it suppresses IL‑6‑induced lung pSTAT3 (ED₅₀ ≈ 3 μg/animal) and reduces IL‑23‑induced ear swelling by 48% as a 4% topical formulation. Safety studies show no genetic toxicity, no hERG inhibition, and no cough signal in sensory nerve assays. PF‑06263276 has been advanced as a clinical candidate for inhaled COPD therapy and topical psoriasis therapy.| Targets |
Pan-Janus kinase (JAK) inhibitor. IC50 values at 1 mM ATP: JAK1 0.8 nM, JAK2 7.9 nM, JAK3 16.7 nM, TYK2 15.3 nM [1].
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| ln Vitro |
In human whole blood assays, PF-06263276 inhibited STAT phosphorylation induced by various cytokines: IFNα (JAK1/TYK2) with IC50 = 0.62 μM (free IC50 = 0.62 nM), IL-23 (JAK2/TYK2) with IC50 = 4.2 μM (free IC50 = 4.2 nM), IL-4 (JAK1/JAK3) with IC50 = 1.8 μM (free IC50 = 1.8 nM), IL-6 (JAK1/JAK2) with IC50 = 2.1 μM (free IC50 = 2.1 nM), and GM-CSF (JAK2/JAK2) with IC50 = 5.2 μM (free IC50 = 5.2 nM). Free IC50 values were calculated accounting for plasma protein binding (fraction unbound = 0.001) [1].
In a PBMC cellular wash-out assay, PF-06263276 demonstrated a long duration of action with a T1/2 of 9 hours. The compound inhibited IL-2 induced IFNγ release in PBMCs with an IC50 of 47.9 nM [1]. In a kinase selectivity panel of 36 kinases at 1 μM (concentration significantly exceeding JAK cellular and enzymatic IC50 values at 1 mM ATP), only JAK3 was inhibited >85% at this concentration, demonstrating suitable selectivity over non-JAK kinases [1]. |
| ln Vivo |
In Vivo: In a mouse intratracheal pharmacodynamic model of IL-6-induced pSTAT3 response in the lungs (mediated via JAK1/JAK2), PF-06263276 caused a dose-related inhibition of the IL-6-elicited increase in lung pSTAT3, giving an ED50 of approximately 3 μg/animal [1].
In a mouse ear dermal model of IL-23-induced inflammation (psoriasis model), topical application of a 4% solution of PF-06263276 significantly reduced ear swelling by 48% over 11 days following multiple IL-23 injections. Treated mice showed swelling of less than 50 μm, while control mice typically swelled to over 100 μm [1]. Following intratracheal dosing, PF-06263276 (10 μg and above) inhibited phosphorylation of STAT3 in the lung following IL-6 stimulation by 100%. In contrast, a 10 μg dose resulted in no inhibition of STAT5 phosphorylation in the blood following ex vivo GM-CSF stimulation, while a 100 μg dose resulted in less than 50% inhibition, demonstrating significantly greater efficacy in the lung compared to blood (organ-targeted JAK inhibition) [1]. JAK1 occupancy in mouse lung following intratracheal administration of PF-06263276 at 10 μg (ED80 dose) or 100 μg showed significant target occupancy maintained 4 hours post-dose [1]. |
| Enzyme Assay |
Enzyme Assay: JAK enzymatic assays were performed using Caliper microfluidic mobility shift assays to measure inhibition of phosphorylation of a peptide substrate by the appropriate JAK enzyme at 1 mM ATP concentration. IC50 values reported represent geometric mean values of a minimum of three determinations [1].
Kinase selectivity profiling was conducted against a panel of 36 kinases at 1 μM compound concentration at the ATP Km concentration. Heat maps showing percent inhibition were generated [1]. |
| Cell Assay |
Cell Assay: For cellular potency in PBMCs, inhibition of interferon γ (IFNγ) release following stimulation with interleukin 2 (IL-2) was measured. IC50 values represent geometric mean values of a minimum of three determinations [1].
For cellular duration of action (DoA) studies, PBMCs were incubated with compounds for 1 hour at 10-fold the IC50, washed extensively, and then recovery of the cellular pSTAT5 response to IL-2 stimulation was monitored over time [1]. For human whole blood assays, inhibition of STAT phosphorylation induced by cytokines (IFNα, IL-23, IL-4, IL-6, GM-CSF) was measured in specific subpopulations of white blood cells. IC50 values were determined, and free IC50 values were calculated by taking into account plasma protein binding (fraction unbound in plasma = 0.001) [1]. |
| Animal Protocol |
Animal Protocol: For the mouse intratracheal pharmacodynamic model, PF-06263276 was dosed as a solution via the intratracheal (i.t.) route. IL-6 was administered i.t. to induce pSTAT3 response in the lungs. Lung pSTAT3 levels were measured. ED50 was calculated as approximately 3 μg/animal [1].
For the mouse ear dermal model, a 4% solution of PF-06263276 in a topical formulation (containing propylene glycol 30%, polyethylene glycol 400 30%, dimethyl isosorbide 10%, glycerin 25.9%, BHA 0.1%) was applied topically to mouse ears. IL-23 was injected into the ear to induce inflammation. Ear swelling was measured over 11 days [1]. For JAK1 occupancy studies, PF-06263276 was administered i.t. at 10 μg or 100 μg. Target occupancy in mouse lung was measured at various time points post-dose [1]. For exploratory toxicology studies, 7-day intravenous toxicology studies were conducted in rats and dogs to assess risk associated with systemic exposure [1]. |
| ADME/Pharmacokinetics |
ADME/Pharmacokinetics: PF-06263276 has a cLogP of 4.4 and log D of 3.9 (measured by shake flask method). Molecular weight is 566 Da, and topological polar surface area (TPSA) is calculated to be 126 Ų. The compound contains a weakly basic imidazole group (pKa = 4.5) and a weakly acidic fluorophenol group (pKa = 8.7) [1].
Following in vitro incubation in human hepatocytes, major metabolites were produced by direct glucuronidation and P450 metabolism. Phenol conjugated metabolites are expected to show no JAK inhibition. This metabolic profile was consistent across rat and dog in vitro hepatocyte and microsomal metabolism studies [1]. In vivo pharmacokinetic properties in rat: iv dose 0.5 mg/kg, CL = 48 mL/min/kg, CLunbound > 48000 mL/min/kg, Vss = 0.8 L/kg, terminal T1/2 = 2.1 h, oral bioavailability <5%. In dog: iv dose 0.1 mg/kg (30 min infusion), CL = 18 mL/min/kg, CLunbound > 18000 mL/min/kg, Vss = 1.0 L/kg, terminal T1/2 = 2.0 h. Plasma protein binding ≥99.9% (fraction unbound = 0.001) [1]. On the basis of human in vitro data and in vivo rat and dog PK data, the compound was predicted to be cleared in humans by glucuronidation and CYP3A4 metabolism, exhibiting low levels of unbound circulating parent following inhaled or dermal delivery due to high unbound clearance. Due to negligible predicted oral absorption and lack of observed circulating metabolites in animal PK studies, the potential for significant levels of circulating active metabolites in human was deemed low risk [1]. |
| Toxicity/Toxicokinetics |
Toxicity/Toxicokinetics: PF-06263276 was screened at 10 μM in a panel of receptors, transporters, enzymes, and ion channels. Greater than 50% inhibition was observed against a small number of targets: 5-HT7, Ab1 kinase, acetylcholinesterase, α2B adrenergic receptor, AurA/Aur2 kinase, KDR kinase, Lck kinase, and Na⁺ channel (site 2). These activities were observed at multiples of >100-fold above the projected free systemic plasma exposures at the maximum clinical lung dose (200 μg), so no consequences were anticipated at clinically relevant exposures. The compound had no effects on hERG potassium current at 1 μM (<1% inhibition) [1].
In the mouse A delta fiber sensory nerve preparation, PF-06263276 was dosed up to 2 mg in 400 μL of micelle vehicle; no nerve activation was detected, providing evidence of low risk for cough effects [1]. In exploratory 7-day intravenous toxicology studies in rats and dogs, there were no adverse test article-related findings. A 36-fold margin was achieved in rat over total plasma AUC based on projected exposure following a human clinical lung dose of 200 μg, and a 55-fold margin was achieved in dog plasma AUC. The BioLum Ames bacterial mutagenicity assay showed no evidence of genetic toxicity with and without metabolic activation. The CHO in vitro micronucleus test also showed no genetic toxicity. Peripheral blood micronucleus assessment from the rat 7-day intravenous study showed no evidence of genetic toxicity [1]. |
| References | |
| Additional Infomation |
PF-06263276 is a potent pan-JAK inhibitor with a type 1.5 binding mode to JAK2, as confirmed by X-ray cocrystal structure (PDB entry 5TQ8). The compound was designed for inhaled or topical delivery to treat inflammatory diseases of the lungs (e.g., COPD) and skin (e.g., mild-to-moderate psoriasis), while avoiding systemic JAK inhibition. It has a long cellular duration of action (T1/2 = 9 h in PBMC wash-out assay) [1].
The compound has a crystalline solid form with very low hygroscopicity and is chemically stable at room temperature and at 40°C with 75% relative humidity for up to 6 weeks. It is stable to jet milling to provide solid material with regular particle size in the respirable range (~2 μm) and is chemically and physically stable when blended with lactose for up to 4 weeks, demonstrating suitability for use in a dry powder inhalation device. It is also amenable to preparation as a 4% solution in a base formulation for topical skin applications [1]. The compound was nominated as a development candidate for an inhaled therapy for COPD and a topical therapy for psoriasis [1]. |
| Molecular Formula |
C31H31FN8O2
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|---|---|
| Molecular Weight |
566.6286
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| Exact Mass |
566.255
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| Elemental Analysis |
C, 65.71; H, 5.51; F, 3.35; N, 19.78; O, 5.65
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| CAS # |
1421502-62-6
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| PubChem CID |
135567296
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| Appearance |
White to off-white solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
42
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| Complexity |
941
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=C(C([H])=C(C([H])([H])C([H])([H])[H])C(=C1[H])C1C([H])=C([H])C2=C(C=1[H])N([H])N=C2C1=NC2=C(C([H])([H])N(C(C3=C([H])N=C(C([H])=N3)N3C([H])([H])C([H])([H])C([H])([H])C([H])([H])C3([H])[H])=O)C([H])([H])C2([H])[H])N1[H])O[H]
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| InChi Key |
XDJGNPSZQSWJCV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H31FN8O2/c1-2-18-13-27(41)22(32)14-21(18)19-6-7-20-24(12-19)37-38-29(20)30-35-23-8-11-40(17-26(23)36-30)31(42)25-15-34-28(16-33-25)39-9-4-3-5-10-39/h6-7,12-16,41H,2-5,8-11,17H2,1H3,(H,35,36)(H,37,38)
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| Chemical Name |
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone
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| Synonyms |
PF-06263276; PF-6263276; PF 6263276; PF-06263,276; 1421502-62-6; 86YZ7HCC8V; (2-(6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-3H-imidazo(4,5-C)pyridin-5(4H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone; Methanone, (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo(4,5-C)pyridin-5-yl)(5-(1-piperidinyl)-2-pyrazinyl)-; PF 06263276; PF06263276; PF6263276.
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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 : ~33.33 mg/mL (~58.82 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 | 1.7648 mL | 8.8241 mL | 17.6482 mL | |
| 5 mM | 0.3530 mL | 1.7648 mL | 3.5296 mL | |
| 10 mM | 0.1765 mL | 0.8824 mL | 1.7648 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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