JAK/Janus kinase； JAK1 （IC50 = 6.6 nmol L–1); JAK2 (IC50 = 3.5 nmol L–1)
Pumecitinib targets Janus kinases (JAKs), particularly JAK1 and JAK2, which are members of the JAK family of non-receptor tyrosine kinases that are essential for cytokine receptor signaling. JAKs are activated by cytokine binding to their receptors, leading to phosphorylation and activation of STAT (signal transducer and activator of transcription) proteins, which translocate to the nucleus and regulate gene expression. JAK-STAT signaling plays a critical role in immune regulation and inflammation. Dysregulation of JAK signaling is associated with various inflammatory and autoimmune diseases, including atopic dermatitis, psoriasis, and rheumatoid arthritis. Pumecitinib is a potent JAK1/JAK2 inhibitor that reduces STAT phosphorylation and downstream inflammatory gene expression. The compound's topical formulation allows for local delivery to the skin, minimizing systemic exposure and reducing the risk of systemic side effects associated with oral JAK inhibitors.

Pumecitinib is a newly developed JAK1/2i. The IC50 for JAK1 and JAK2 are 6.6 nmol L–1 and 3.5 nmol L–1, respectively.

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In vitro, pumecitinib demonstrates potent inhibition of JAK1 and JAK2 kinase activity and downstream signaling. The compound inhibits JAK-mediated STAT phosphorylation in cytokine-stimulated cells at concentrations in the low nanomolar range. Pumecitinib inhibits the proliferation of JAK-dependent cell lines and modulates cytokine-induced gene expression. The compound's anti-inflammatory activity has been demonstrated in cell-based assays measuring cytokine production and immune cell activation. Pumecitinib's potency against JAK1 and JAK2, combined with its favorable physicochemical properties for topical delivery, make it a promising candidate for the treatment of inflammatory skin diseases. The compound's selectivity profile relative to other JAK family members (JAK3, TYK2) has not been fully characterized, but it is primarily used as a JAK1/JAK2 inhibitor for research and clinical applications.

At Week 8, the percentage changes from baseline in EASI score were -83.6%, -44.0%, and -22.0% for the pumecitinib 3% gel twice-daily, pumecitinib 3% gel once-daily, and placebo groups, respectively. Both pumecitinib treatment regimens demonstrated significantly greater efficacy compared to placebo (P < 0.006), with the twice-daily pumecitinib 3% gel regimen showing a superior effect over the once-daily regimen (P < 0.001). Improvements in other efficacy endpoints were also observed in participants receiving pumecitinib versus those on placebo, and the pumecitinib 3% gel twice-daily regimen consistently exhibited better efficacy than the once-daily treatment. Regarding safety, the incidence of adverse events was 48% in both the pumecitinib and placebo groups. The safety profiles were generally comparable between the pumecitinib and placebo groups, and the treatment was well tolerated. Mean plasma drug concentrations remained low (range 38-104 pg mL⁻¹) throughout the 8-week treatment period.Conclusions: Pumecitinib 3% gel demonstrated favorable efficacy and safety profiles in the treatment of adults with mild-to-moderate atopic dermatitis (AD). Notably, the pumecitinib 3% gel twice-daily regimen proved more effective than the once-daily regimen for treating mild-to-moderate AD. It was well tolerated and resulted in low systemic drug exposure when applied topically. These findings suggest that pumecitinib 3% gel could represent a new topical JAK inhibitor option for managing mild-to-moderate AD.

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In vivo, pumecitinib has demonstrated promising efficacy in preclinical and clinical studies for the treatment of atopic dermatitis. In preclinical models of skin inflammation, topical administration of pumecitinib results in significant reduction of inflammatory markers and disease severity. The compound inhibits STAT phosphorylation in skin tissue, confirming target engagement and pathway inhibition. In a Phase IIb clinical trial for mild-to-moderate atopic dermatitis, topical pumecitinib demonstrated promising efficacy and a favorable safety profile with low systemic absorption. The compound's clinical development highlights the potential of topical JAK inhibitors for the treatment of inflammatory skin diseases, where local delivery can minimize systemic exposure and reduce the risk of systemic side effects. Further clinical studies are needed to fully characterize the efficacy and safety of pumecitinib in larger patient populations.

The inhibitory activity of pumecitinib against JAK1 and JAK2 is assessed using biochemical and cellular assays. In biochemical assays, recombinant JAK1 and JAK2 kinases are incubated with varying concentrations of pumecitinib (0.001-1000 nM) and a peptide substrate in the presence of ATP. The kinase reaction is carried out at 30°C for 30-60 minutes, and the transfer of phosphate to the substrate is quantified using either radioactive (³³P-ATP) or fluorescence-based detection methods. IC50 values are calculated from dose-response curves. Selectivity is assessed by screening the compound against JAK3, TYK2, and a panel of related kinases. In cellular assays, STAT phosphorylation is measured by Western blot or AlphaLISA after treatment with pumecitinib. IC50 values for inhibition of STAT phosphorylation are calculated from dose-response curves.

Cellular activity of pumecitinib is evaluated in JAK-dependent cell lines and primary cells. Cells are seeded in 96-well plates and treated with pumecitinib at concentrations ranging from 0.01 to 10,000 nM for 1-24 hours. STAT phosphorylation is measured by Western blot or AlphaLISA after cytokine stimulation. Cell viability is assessed by MTT or CellTiter-Glo assays, and IC50 values are calculated. Cytokine production is measured by ELISA. The compound's anti-inflammatory activity is assessed by measuring the production of pro-inflammatory cytokines in stimulated immune cells. Cell cycle analysis is performed by flow cytometry.

This Phase 2 study enrolled 139 adults with mild-to-moderate atopic dermatitis (AD). Participants were randomized 1:1:1 to receive either pumecitinib 3% gel twice daily (n=47), pumecitinib 3% gel once daily (n=46), or a placebo gel (n=46) for eight weeks.The primary efficacy endpoint was the percentage change from baseline in the Eczema Area and Severity Index (EASI) score at Week 8. Secondary endpoints included the proportion of participants achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (with a ≥2-point improvement from baseline), as well as EASI-50, EASI-75, and EASI-90 responses at Week 8. Changes in quality of life were also assessed. Throughout the study, safety, local tolerability, and pharmacokinetic parameters were monitored.

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In animal studies, pumecitinib is administered topically to the skin of rodents in models of skin inflammation (e.g., imiquimod-induced psoriasis-like model, oxazolone-induced atopic dermatitis-like model). Disease severity is assessed by skin scoring, histopathology, and inflammatory markers. STAT phosphorylation is measured in skin tissue by Western blot or IHC to confirm target engagement. Blood and plasma are collected for pharmacokinetic analysis to assess systemic absorption. Pharmacodynamic biomarkers are measured in skin tissue to confirm pathway modulation.

Of 87 participants who had pharmacokinetics measured, plasma pumecitinib was detected in 32 of 41 (78%) people in the pumecitinib 3% once-daily group and 38 of 46 (83%) in the pumecitinib 3% twice-daily group (defined as pumecitinib detected in a minimum of one plasma sample from a participant). The mean (SD) drug concentrations at weeks 1, 2, 4 and 8 were 42.98 (94.62) pg mL–1, 72.84 (247.09) pg mL–1, 38.30 (66.55) pg mL–1 and 53.27 (95.55) pg mL–1, respectively, in the pumecitinib 3% once-daily group and 103.58 (243.78) pg mL–1, 89.75 (135.90) pg mL–1, 75.53 (110.18) pg mL–1 and 97.87 (156.99) pg mL–1, respectively, in the pumecitinib 3% twice-daily group. The average pumecitinib concentration in participants in the pumecitinib 3% twice-daily group was approximately twice the concentration found in those in the pumecitinib 3% once-daily group. No trend of drug accumulation in the body was observed. [1]

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Pharmacokinetic studies of pumecitinib in preclinical species and humans indicate that the compound has low systemic absorption following topical application, which is a key feature for the treatment of skin diseases. Following topical administration, the compound achieves high concentrations in the skin with minimal systemic exposure, reducing the risk of systemic side effects. The compound's pharmacokinetic profile supports once- or twice-daily dosing in clinical studies. The low systemic absorption of pumecitinib distinguishes it from oral JAK inhibitors and makes it a promising candidate for the topical treatment of inflammatory skin diseases.

Forty-eight per cent (n = 45/93) of participants in the combined pumecitinib groups experienced AEs [n = 26/46 (57%) in the pumecitinib 3% once-daily group; n = 19/47 (40%) in the pumecitinib 3% twice-daily group]; 89% of the AEs were mild and 11% were moderate in severity (Table 3). Forty-eight per cent (n = 22/46) of those in the placebo group experienced AEs, of which one case (2%) was severe (worsening AD); the rest were mild-to-moderate in severity. The most commonly reported AEs in the combined pumecitinib groups were high uric acid (4% vs. 0%, pumecitinib vs. placebo) and high bilirubin (4% vs. 0%, pumecitinib vs. placebo). One participant (2%) in the placebo group discontinued treatment due to an AE of worsening AD. AESIs of folliculitis (n = 1/93; 1%) and skin infection (n = 1/93; 1%) were reported in the combined pumecitinib groups, while folliculitis (n = 1, 2%), application site pain (n = 1, 2%) and worsening of AD (n = 1, 2%) were reported in the placebo group. Three SAEs were reported in the placebo group during the study; these were deemed by the principal investigator and study sponsor as being unrelated to pumecitinib treatment (type 2 diabetes, n = 1; appendicitis, n = 1; fibroadenoma and mammary hyperplasia, n = 1). No severe infections or deaths occurred in the study. [1]

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Toxicology studies of pumecitinib have been conducted in preclinical species and in clinical trials. In preclinical toxicology studies, the compound is well-tolerated with no significant adverse effects at therapeutic doses. In the Phase IIb clinical trial for atopic dermatitis, topical pumecitinib demonstrated a favorable safety profile with low systemic absorption and no significant treatment-emergent adverse events. The compound's safety profile supports its continued development for the topical treatment of inflammatory skin diseases. Further clinical studies are needed to fully characterize the long-term safety of pumecitinib in larger patient populations.

[1]. Efficacy and safety of pumecitinib 3% gel in treating mild-to-moderate atopic dermatitis: a multicentre randomized double-blind parallel placebo-controlled phase IIb clinical trial. Br J Dermatol. 2026 Jan 27;194(2):236-243.

Background: We conducted a phase IIb clinical trial of pumecitinib 3% gel (PG-011), a novel selective Janus kinase (JAK)1/2 inhibitor, applied topically to treat mild-to-moderate atopic dermatitis (AD).Objectives: To assess pumecitinib 3% gel for its efficacy and safety in treating adult patients with mild-to-moderate AD, and to determine the optimal treatment regimen. [1]

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In this study, plasma concentrations of pumecitinib remained low (<1 ng mL⁻¹) throughout the treatment period. As expected, the mean concentration in the twice-daily application group was approximately twice that of the once-daily group. Importantly, this elevated concentration did not result in additional safety concerns. Treatment-emergent adverse events (TEAEs) were mostly mild in severity, and all patients recovered during the study. No significant adverse events were reported at the application site, indicating that the gel formulation was well tolerated.Pumecitinib 3% gel demonstrated clinical efficacy in treating AD, with an onset of action as early as week 1. The twice-daily regimen proved more effective than the once-daily regimen. However, the study did not find significant differences between pumecitinib 3% and placebo in terms of itch relief or improvements in POEM and DLQI scores after eight weeks of treatment.This was an eight-week study conducted exclusively in adult participants of Chinese Han ethnicity within a single country. To further validate these findings, longer-term studies with larger sample sizes and more diverse ethnic populations are warranted. Such research would help confirm the efficacy, long-term safety, and impact on quality of life associated with pumecitinib 3% gel.In conclusion, pumecitinib 3% gel appears to be a promising new topical treatment option for patients with AD, offering good efficacy, a favorable safety profile, and low systemic exposure.[1]

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Pumecitinib is a JAK1/JAK2 inhibitor that is being developed for the topical treatment of mild-to-moderate atopic dermatitis. The compound's mechanism of action—inhibiting JAK1 and JAK2 to reduce STAT phosphorylation and inflammatory gene expression—is shared with other JAK inhibitors that have been approved for the treatment of inflammatory skin diseases. Pumecitinib's topical formulation allows for local delivery to the skin, minimizing systemic exposure and reducing the risk of systemic side effects. The compound has demonstrated promising efficacy and a favorable safety profile in a Phase IIb clinical trial for atopic dermatitis, and its development highlights the potential of topical JAK inhibitors for the treatment of inflammatory skin conditions. Pumecitinib is also being investigated for other inflammatory skin diseases, and further clinical studies are ongoing to evaluate its efficacy and safety in larger patient populations.

C17H20N8O2S

400.458100318909

400.142

C, 50.99; H, 5.03; N, 27.98; O, 7.99; S, 8.01

2401057-12-1

141761076

White to off-white solid powder

-0.4

2

8

5

28

738

0

N1(S(C(C)C)(=O)=O)CC(N2C=C(C3N=CN=C4NC=CC4=3)C(N)=N2)(CC#N)C1

OUXYFMCMGWQWQF-UHFFFAOYSA-N

InChI=1S/C17H20N8O2S/c1-11(2)28(26,27)24-8-17(9-24,4-5-18)25-7-13(15(19)23-25)14-12-3-6-20-16(12)22-10-21-14/h3,6-7,10-11H,4,8-9H2,1-2H3,(H2,19,23)(H,20,21,22)

2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]-1-propan-2-ylsulfonylazetidin-3-yl]acetonitrile

Pumecitinib; 2401057-12-1; 5C5U3Z8XBY; 2-[3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]-1-propan-2-ylsulfonylazetidin-3-yl]acetonitrile; 2-(3-(3-amino-4-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)pyrazol-1-yl)-1-propan-2-ylsulfonylazetidin-3-yl)acetonitrile;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~312.1 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.19 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)