Fedratinib hydrochloride hydrate is an effective, selective, ATP competitive and orally active JAK2 inhibitor, and the IC50 values for both JAK2 and JAK2V617F kinases are 3nM[1]. Fedratinib hydrochloride hydrate inhibits the carrier-mediated uptake and transcellular flux of thiamine in cell[2]. Fedratinib hydrochloride hydrate has been widely used to inhibit the progression of solid tumors and as a model compound for developing new JAK target inhibitors[3].
In vitro, Fedratinib hydrochloride hydrate treatment for 48 hours significantly inhibited the viability of HMC-1.2 cells, with an IC50 value of 3.74µM[4]. Fedratinib hydrochloride hydrate treatment at 3μM for 10 days significantly inhibited the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSC-TERT) that overexpressed the human telomerase reverse transcriptase gene (TERT), resulting in a significant reduction in mineralized matrix formation and a decrease in the expression of JAK2, STAT5, and STAT3[5]. Treatment with 5µM of Fedratinib hydrochloride hydrate for 24 hours reduced the cell migration and invasion abilities of SKOV3 cells, and arrested the cell cycle at the G1 phase[6].
In vivo, Fedratinib hydrochloride hydrate was administered orally by gavage at a dose of 120mg/kg, twice daily for 42 days, which significantly improved the survival rate of a murine model of myeloproliferative disease induced by JAK2V617F mutation, and inhibited splenomegaly and erythrocytosis[7]. A single oral administration of Fedratinib hydrochloride hydrate (60mg/kg) for 24 hours significantly reduced the IFN-γ-induced STAT1 phosphorylation in the peritoneal macrophages of mice[8].
References:
[1] Talpaz M, Kiladjian J J. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis[J]. Leukemia, 2021, 35(1): 1-17.
[2] Zhang Q, Zhang Y, Diamond S, et al. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy[J]. Drug Metabolism and Disposition, 2014, 42(10): 1656-1662.
[3] Qiu Q, Chi F, Zhou D, et al. Exploration of Janus kinase (JAK) and histone deacetylase (HDAC) bispecific inhibitors based on the moiety of fedratinib for treatment of both hematologic malignancies and solid cancers[J]. Journal of Medicinal Chemistry, 2023, 66(8): 5753-5773.
[4] Makeeva A, Stivala S, Ratti E, et al. Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells[J]. American Journal of Cancer Research, 2025, 15(1): 84.
[5] AlMuraikhi N, Alaskar H, Binhamdan S, et al. JAK2 inhibition by fedratinib reduces osteoblast differentiation and mineralisation of human mesenchymal stem cells[J]. Molecules, 2021, 26(3): 606.
[6] Dong Y, Deng Y, Zhu L, et al. Fedratinib inhibits ovarian cancer progression by downregulating QPCT expression[J]. Discover Oncology, 2025, 16(1): 1865.
[7] Wernig G, Kharas M G, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera[J]. Cancer cell, 2008, 13(4): 311-320.
[8] Keenan C, Albeituni S, Oak N, et al. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis[J]. Blood, 2024, 143(23): 2386-2400.
Fedratinib hydrochloride hydrate是一种有效、选择性、ATP竞争性且可口服的JAK2抑制剂，对JAK2和JAK2V617F激酶的IC50值均为3nM[1]。Fedratinib hydrochloride hydrate可抑制细胞中硫胺素的载体介导摄取和跨细胞转运[2]。Fedratinib hydrochloride hydrate已被广泛用于抑制实体瘤的进展，并作为开发新型JAK靶点抑制剂的模型化合物[3]。
在体外，Fedratinib hydrochloride hydrate处理48小时显著抑制了HMC-1.2细胞的活力，IC50值为3.74µM[4]。使用3µM的Fedratinib hydrochloride hydrate处理10天，显著抑制了过表达人端粒酶逆转录酶基因（TERT）的人骨髓间充质干细胞（hBMSC-TERT）的成骨分化，导致矿化基质形成显著减少，并降低了JAK2、STAT5和STAT3的表达[5]。使用5µM的Fedratinib hydrochloride hydrate处理24小时，降低了SKOV3细胞的迁移和侵袭能力，并使细胞周期停滞在G1期[6]。
在体内，每日两次通过灌胃口服给予120mg/kg剂量的Fedratinib hydrochloride hydrate，持续42天，显著提高了由JAK2V617F突变诱导的骨髓增殖性疾病小鼠模型的存活率，并抑制了脾肿大和红细胞增多症[7]。单次口服60mg/kg剂量的Fedratinib hydrochloride hydrate 24小时，显著降低了小鼠腹腔巨噬细胞中IFN-γ诱导的STAT1磷酸化[8]。