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Purity: ≥98%
Brepocitinib (PF06700841; PF-06700841) is a potent, selective, and conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor of TYK2 and JAK1 kinases with anti-inflammatory effects. It inhibits TYK2 and JAK1 with IC50 values of 23 nM and 17 nM respectively. PF-06700841 is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868) as a potential therapeutic for the treatment of systemic lupus erythematosus and plaque psoriasis. Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies. PF-06700841was safe and well tolerated up to 200 mg once daily in healthy subjects and 100 mg once daily in patients with psoriasis, suggesting potential therapeutic utility in plaque psoriasis and other inflammatory diseases.
| Targets |
Brepocitinib (PF-06700841) is a dual inhibitor of TYK2 and JAK1.
TYK2 IC₅₀ = 23 nM (enzymatic, ATP = 1 mM) JAK1 IC₅₀ = 17 nM (enzymatic, ATP = 1 mM) JAK2 IC₅₀ = 77 nM (enzymatic, ATP = 1 mM) JAK3 IC₅₀ = 6494 nM (enzymatic, ATP = 1 mM) VEGFR2 (KDR) IC₅₀ = 1600 nM (enzymatic, at ATP Km) |
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| ln Vitro |
With human whole blood (HWB) IC50s of 65 and 120 nM, respectively, brepocitinib (PF-06700841; Compound 23) potently inhibits TYK2/JAK2 mediated IL-12/pSTAT4 and IL-23/pSTAT3[1]. Brepocitinib inhibits IL6/pStat1 in the CD3+ cellular subset with good potency (IC50 of 81 nM), whereas it inhibits IL6/pSTAT3 with lower potency (IC50 of 641 nM) in the same CD3+ cellular subset[1]. Brepocitinib also exhibits a moderate level of effectiveness in inhibiting the JAK1/JAK3 driven γ- common chain cytokines, as demonstrated by IL-15/pStat5 and IL-21/pSTAT3 (HWB IC50s of 238 and 204 nM, respectively)[1]. In HWB spiked with CD34+ progenitor cells, brepocitinib inhibits EPO/pSTAT5 (JAK2 homodimer) with an IC50 of 577 nM. Brepocitinib also inhibits IL10/pSTAT3 (TYK2/JAK1) and IL27/pSTAT3 (JAK1/JAK2/TYK2), with IC50s of 305 nM and 86 nM, respectively[1].
Brepocitinib potently inhibits TYK2 and JAK1 with IC₅₀ values of 23 nM and 17 nM, respectively, in enzymatic assays at 1 mM ATP. It shows selectivity over JAK2 (IC₅₀ = 77 nM) and JAK3 (IC₅₀ = 6494 nM). In human whole blood assays, it inhibits IFNα-induced pSTAT3 with an IC₅₀ of 30 nM (free IC₅₀ = 13 nM). It also inhibits IL-12/pSTAT4 (IC₅₀ = 65 nM), IL-23/pSTAT3 (IC₅₀ = 120 nM), IL-6/pSTAT1 (IC₅₀ = 81 nM), IL-15/pSTAT5 (IC₅₀ = 238 nM), IL-21/pSTAT3 (IC₅₀ = 204 nM), IL-10/pSTAT3 (IC₅₀ = 305 nM), IL-27/pSTAT3 (IC₅₀ = 86 nM), and EPO/pSTAT5 (IC₅₀ = 577 nM). In a kinase selectivity panel (306 kinases), at 1 µM concentration and ATP at Km, 21 kinases showed >50% inhibition, including TYK2, JAK1, JAK2, AurA/TYX, TNK1, JAK3, QIK, ACK, PDGFRα, SIK, MAP2K5, MNK2, PDGFRβ, ERK5, Nualk1, FMS, MARK4, and MARK3. At 1 mM ATP, only TYK2, JAK1, JAK2, and TNK1 showed >50% inhibition. In a CEREP wide ligand profile screen at 10 µM, no significant off-target activity was observed except for VEGFR2 (IC₅₀ = 1600 nM in enzymatic assay, but >30 µM in cell-based assay). |
| ln Vivo |
The oral delivery of brepocitinib (PF-06700841; Compound 23) to female Lewis rats for seven consecutive days considerably lowers the rise in paw volume in a dose-dependent manner. Animals given Brepocitinib were given the following plasma concentrations at peak (30 min) and trough (24 h) time intervals after the final dose: 3 mg/kg, 3.54 μM, 0.0221 μM; 10 mg/kg, 10.95 μM, 0.06 μM; and 30 mg/kg, 23.89 μM, 0.06 μM[1].
Brepocitinib showed dose-dependent efficacy in a rat adjuvant-induced arthritis model. Oral administration of 3, 10, and 30 mg/kg/day significantly reduced hind paw swelling compared to vehicle. Plasma concentrations at peak (30 min) and trough (24 h) after the final dose were: 3 mg/kg: 3.54 µM and 0.022 µM; 10 mg/kg: 10.95 µM and 0.06 µM; 30 mg/kg: 23.89 µM and 0.06 µM. |
| Enzyme Assay |
The enzymatic activity of Brepocitinib against JAK family kinases was determined using a microfluidic mobility shift assay. Recombinant human kinase domains (JAK1, JAK2, JAK3, TYK2) were incubated with a fluorescently labeled peptide substrate and ATP at either the apparent Km for each kinase or at a fixed concentration of 1 mM ATP. Reactions were stopped with EDTA, and phosphorylation levels were measured via mobility shift. IC₅₀ values were calculated from dose-response curves.
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| Cell Assay |
Cellular potency and selectivity were evaluated in human whole blood assays. Fresh heparinized whole blood from healthy donors was treated with compound and stimulated with specific cytokines (e.g., IFNα, IL-6, IL-12, IL-23, EPO) at EC₉₀–EC₉₅ concentrations. After stimulation, cells were fixed, permeabilized, stained with phospho-STAT antibodies, and analyzed by flow cytometry. IC₅₀ values were derived from inhibition curves of STAT phosphorylation.
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| Animal Protocol |
Animal/Disease Models: Female Lewis rats with induced arthritis[1]
Doses: 3 mg/kg, 10 mg/kg, or 30 mg/kg Route of Administration: Oral administration; for 7 days Experimental Results: Increased in paw volume was Dramatically lower and dose-dependent. The rat adjuvant-induced arthritis model was used to evaluate efficacy. Female Lewis rats were immunized with complete Freund’s adjuvant. Once hind paw volume increased by ≥0.2 mL, rats were enrolled and dosed orally with Brepocitinib p-tosylate salt (3, 10, 30 mg/kg/day) or vehicle (2% Tween 80/0.5% methylcellulose in water) for 7 consecutive days. Paw volume was measured daily. Blood was collected at peak (15 min post-dose) and trough (24 h post-dose) for PK and STAT phosphorylation analysis. |
| ADME/Pharmacokinetics |
Brepotinib exhibits high passive permeability (RRCK Papp = 18.8 × 10⁻⁶ cm/s). In Sprague-Dawley rats, after intravenous administration of 1 mg/kg and oral administration of 3 mg/kg tosylate, the clearance was 31 mL/min/kg, the volume of distribution was 2.0 L/kg, and the oral bioavailability was 83%. Cmax was 774 ng/mL, and AUC was 1340 ng·h/mL. In vitro systemic predictions for human data: plasma clearance <3.9 mL/min/kg (human liver microsomes), volume of distribution ~1.7 L/kg. Plasma protein binding was low (human fᵤ = 0.61, rat fᵤ = 0.69). Metabolism is primarily via CYP450 (CYP3A4), with low turnover in human hepatocytes (Clint < 0.6 µL/min/million cells).
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| Toxicity/Toxicokinetics |
At a concentration of 10 µM, screening of various receptors/ion channels revealed no significant off-target activity, with only weak inhibition of VEGFR2 observed (IC₅₀ = 1600 nM, non-functional intracellularly). In kinase-selective screening, no significant off-target kinase inhibition was observed at physiologically relevant ATP concentrations. Based on previous data on JAK inhibitors, hematological changes (e.g., decreased hemoglobin) induced by JAK2 inhibition are considered manageable.
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| References | |
| Additional Infomation |
PF-06700841 is currently undergoing clinical trial NCT03236493 (Safety and pharmacokinetic study of PF-06700841 in healthy volunteers in Japan). Brepocitinib is an orally potent, selective, non-receptor tyrosine protein kinase inhibitor of TYK2 (tyrosine kinase 2) and JAK1 (Janus kinase 1; JAK1), with potential immunomodulatory and anti-inflammatory activity. After oral administration, brepocitinib selectively binds to and inhibits the activation of TYK2 and JAK1, thereby blocking TYK2 and JAK-1-dependent cytokine signaling. This may reduce inflammatory responses and prevent inflammatory damage caused by certain autoimmune diseases. TYK2 and JAK-1 are both non-receptor tyrosine kinases belonging to the Janus kinase family and are involved in signaling pathways affecting hematopoiesis, immunity, and inflammation. Brepocitinib is an orally administered TYK2/JAK1 dual inhibitor specifically designed for autoimmune diseases. It combines JAK1 inhibition (affecting γ-common chain cytokines, IL-6, and type I interferon) and TYK2 inhibition (blocking IL-12, IL-23, and type I interferon). The goal is to minimize JAK2-mediated hematopoietic side effects while improving efficacy. This compound has completed Phase I clinical trials and is currently undergoing Phase II clinical trials (NCT02969018, NCT02958865, NCT03395184, NCT02974868) for the treatment of psoriasis, psoriatic arthritis, and other inflammatory diseases.
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| Molecular Formula |
C18H21F2N7O
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|---|---|
| Molecular Weight |
389.402449369431
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| Exact Mass |
389.18
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| Elemental Analysis |
C, 55.52; H, 5.44; F, 9.76; N, 25.18; O, 4.11
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| CAS # |
1883299-62-4
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| Related CAS # |
Brepocitinib P-Tosylate;2140301-96-6
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| PubChem CID |
118878093
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
609
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CN1C=C(C=N1)NC2=NC=CC(=N2)N3C[C@H]4CC[C@@H](C3)N4C(=O)[C@@H]5CC5(F)F
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| InChi Key |
BUWBRTXGQRBBHG-MJBXVCDLSA-N
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| InChi Code |
InChI=1S/C18H21F2N7O/c1-25-8-11(7-22-25)23-17-21-5-4-15(24-17)26-9-12-2-3-13(10-26)27(12)16(28)14-6-18(14,19)20/h4-5,7-8,12-14H,2-3,6,9-10H2,1H3,(H,21,23,24)/t12-,13+,14-/m0/s1
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| Chemical Name |
[(1S)-2,2-difluorocyclopropyl]-[(1R,5S)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone
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| Synonyms |
PF 6700841; PF-06700,841; Brepocitinib; PF06700,841; PF-6700841; PF6700841; PF-06700,841
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 | 2.5681 mL | 12.8403 mL | 25.6805 mL | |
| 5 mM | 0.5136 mL | 2.5681 mL | 5.1361 mL | |
| 10 mM | 0.2568 mL | 1.2840 mL | 2.5681 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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