Itacitinib是一种JAK1抑制剂（IC50=2nM），Itacitinib可通过选择性抑制JAK1酪氨酸激酶以调节JAK-STAT信号通路，同时通过减少促炎细胞因子的产生以调控免疫反应。
Cas No.:1334298-90-6
Sample solution is provided at 25 µL, 10mM.
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Itacitinib is a JAK1 inhibitor (IC₅₀=2nM). Itacitinib selectively inhibits JAK1 tyrosine kinase to modulate the JAK-STAT signaling pathway while regulating immune responses by reducing the production of pro-inflammatory cytokines[1-2]. Itacitinib can be used in research related to myelofibrosis, graft-versus-host disease (GVHD), and cytokine release syndrome (CRS)[3-4].
In vitro, human CAR-T cells (including GD2, EGFR, and CD19 constructs) were pretreated with Itacitinib (100–250nM) and cultured under anti-CD3/CD28 antibody activation conditions. Itacitinib did not inhibit T cell proliferation and maintained the specific killing activity of CAR-T cells against target tumor cells (SY5Y neuroblastoma cells)[5]. Mouse colon cancer cells CT26.WT were pretreated with Itacitinib (0.5μM) for 2 hours and then co-cultured with IFN-γ (100ng/mL). Itacitinib significantly inhibited IFN-γ-induced phosphorylation of JAK1/STAT1 and cleavage of caspase-3, while reducing the apoptosis rate. Itacitinib blocked the JAK-STAT signaling pathway, thereby inhibiting IFN-γ-mediated pro-apoptotic effects[6].
In vivo, Itacitinib (120mg/kg) was administered twice daily via oral gavage to xenograft graft-versus-host disease (xGVHD) model mice induced by intravenous injection of 2×10⁷ human peripheral blood mononuclear cells (hPBMCs) from day 3 to day 28 post-transplantation. Itacitinib significantly prolonged the median survival of the model mice, reduced the absolute numbers of human CD4⁺ T cells and human CD8⁺ T cells in peripheral blood, and increased the frequency of human regulatory T cells (Tregs) among CD4⁺ T cells[7]. In a secondary hemophagocytic lymphohistiocytosis (HLH) model induced by CpG/αIL-10R, Itacitinib (120mg/kg; twice daily) was administered from days 4 to 8 post-induction. Itacitinib significantly improved mouse survival rates, enhanced clinical scores, and reduced serum levels of cytokines such as CXCL10, IL-12, IL-6, and GM-CSF, as well as the number of neutrophils in the spleen[8].
References:
[1] Mascarenhas JO, Talpaz M, Gupta V, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017 Feb;102(2):327-335.
[2] Lescoat A, Lelong M, Jeljeli M, et al. Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease. Biochem Pharmacol. 2020 Aug;178:114103.
[3] Chen X, Xun Z, Yuska B, et al. Itacitinib Population Pharmacokinetics and Exposure-Response in Patients With Acute Graft-Versus-Host Disease. J Clin Pharmacol. 2023 May;63(5):622-632.
[4] Etra A, Capellini A, Alousi A, et al. Effective treatment of low-risk acute GVHD with itacitinib monotherapy. Blood. 2023 Feb 2;141(5):481-489.
[5] Huarte E, O'Connor RS, Peel MT, et al. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309.
[6] Yang X, Gao DD, Zhang H, et al. Combining Radiation and anti-PD-L1 Enhances the Antitumor Activity in Colorectal Cancer via IFN-γ-Dependent Activation of STAT1. Technol Cancer Res Treat. 2025 Jan-Dec;24:15330338251406931.
[7] Courtois J, Ritacco C, Dubois S, et al. Itacitinib prevents xenogeneic GVHD in humanized mice. Bone Marrow Transplant. 2021 Nov;56(11):2672-2681.
[8] Keenan C, Albeituni S, Oak N, et al. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis. Blood. 2024 Jun 6;143(23):2386-2400.
Itacitinib是一种JAK1抑制剂（IC50=2nM），Itacitinib可通过选择性抑制JAK1酪氨酸激酶以调节JAK-STAT信号通路，同时通过减少促炎细胞因子的产生以调控免疫反应[1-2]。Itacitinib可用于骨髓纤维化、移植物抗宿主病（GVHD）及细胞因子释放综合征（CRS）的相关研究[3-4]。
在体外，Itacitinib（100–250nM）预处理人源CAR T细胞（包括GD2、EGFR和CD19构建体）在抗CD3/CD28抗体激活条件下培养，Itacitinib不会抑制T细胞增殖，且维持CAR T细胞对靶肿瘤细胞（SY5Y神经母细胞瘤细胞）的特异性杀伤活性[5]。Itacitinib（0.5μM）预处理小鼠结肠癌细胞CT26.WT 2小时，随后与IFN-γ（100ng/mL）共培养，Itacitinib显著抑制IFN-γ诱导的JAK1/STAT1磷酸化及caspase-3切割，并降低细胞凋亡率，Itacitinib阻断JAK-STAT信号通路抑制IFN-γ介导的促凋亡效应[6]。
在体内，Itacitinib（120mg/kg）每日两次灌胃给药，用于处理经2×107人外周血单核细胞（hPBMC）静脉注射诱导的异种移植物抗宿主病小鼠（从移植后第3天开始至第28天）。Itacitinib显著延长了模型小鼠的中位生存期，降低了外周血中人CD4+ T细胞和人CD8+ T细胞的绝对数量，并提高了人调节性T细胞（Treg）在CD4+ T细胞中的频率[7]。Itacitinib（120mg/kg；每日两次）于CpG/αIL-10R诱导的继发性噬血细胞性淋巴组织细胞增生症小鼠发病后第4至8天给药，Itacitinib显著提高小鼠生存率、改善临床评分，降低血清CXCL10、IL-12、IL-6、GM-CSF等细胞因子水平及脾脏中性粒细胞数量[8]。
| Cell experiment [1]: | |
Cell lines | CT26.WT murine colon carcinoma cells |
Preparation Method | CT26.WT cells were treated with the JAK1 inhibitor Itacitinib (0.5μM) for 6 hours. To directly test the requirement of STAT1 signaling, cells were pre-treated with Itacitinib prior to stimulation with interferon-gamma (IFN-γ, 100ng/mL) or a combination of ionizing radiation (IR, 6Gy) and IFN-γ. |
Reaction Conditions | 0.5μM; 6h pre-treatment before stimulation with IFN-γ |
Applications | Pharmacologic inhibition of JAK1 by Itacitinib abolished IFN-γ-induced and IR+IFN-γ-induced phosphorylation of STAT1 and cleavage of caspase-3 in CT26.WT cells. IR and IFN-γ each significantly increased apoptosis, pre-treatment with Itacitinib abolished these pro-apoptotic effects, reducing apoptosis rates to near-control levels. |
| Animal experiment [2]: | |
Animal models | C57BL/6J mice (wildtype and perforin-deficient Prf1-/- mice) |
Preparation Method | Mice were treated with Itacitinib (120mg/kg) administered by oral gavage twice daily. In the secondary HLH model, WT mice received CpG DNA and anti-IL-10R antibody injections on days 0, 2, 4, and 7, with Itacitinib treatment from days 4 to 8. In the primary HLH model, Prf1-/- mice were infected with lymphocytic choriomeningitis virus (LCMV) and treated with Itacitinib from days 4 to 29 post-infection. Mice were sacrificed on day 9 or 30 for analysis. |
Dosage form | 120mg/kg; oral gavage; twice daily administration. |
Applications | Itacitinib significantly improved survival and clinical scores in CpG-induced secondary HLH, with median survival of 45 days versus 33 days in controls. However, in LCMV-induced primary HLH, Itacitinib provided only partial survival benefit and clinical improvement compared to the superior effects of ruxolitinib (JAK1/2 inhibitor). Itacitinib treatment significantly reduced serum levels of proinflammatory cytokines including CXCL10, IL-12(p70), IL-6, GM-CSF, MCP-1, and MIP-1a, and decreased splenic neutrophil numbers and activation in secondary HLH. RNA-sequencing revealed that Itacitinib targeted inflammatory and metabolic pathway genes in CD8+ T cells but had minimal transcriptional impact on monocytes. |
References: | |
| Cas No. | 1334298-90-6 | SDF | |
| 别名 | 伊他替尼,INCB039110 | ||
| Canonical SMILES | N#CCC1(N2N=CC(C3=C4C(NC=C4)=NC=N3)=C2)CN(C5CCN(C(C6=C(F)C(C(F)(F)F)=NC=C6)=O)CC5)C1 | ||
| 分子式 | C26H23F4N9O | 分子量 | 553.51 |
| 溶解度 | DMSO : ≥ 30 mg/mL (54.20 mM) | 储存条件 | Store at -20°C |
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| 1 mM | 1.8067 mL | 9.0333 mL | 18.0665 mL |
| 5 mM | 361.3 μL | 1.8067 mL | 3.6133 mL |
| 10 mM | 180.7 μL | 903.3 μL | 1.8067 mL |
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