TG101348 (SAR302503)

TG101348 (SAR302503) is a selective small-molecule inhibitor of JAK2 with an IC₅₀ value of 3nM^[1]. TG101348 is primarily approved for myelofibrosis (MF) and is also under active investigation for myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes and chronic neutrophilic leukemia (CNL)^[2].

In vitro, TG101348 (300 and 600nM) preincubation on human erythro-megakaryocytic UT7/Epo cells for 30min prior to stimulation with 10U/ml erythropoietin (EPO) strongly suppressed JAK2-mediated STAT5 phosphorylation and AKT activation, and markedly reduced GATA-1 S310 phosphorylation^[3]. TG101348 (250nM, 500nM and 2μM) application on pancreatic ductal adenocarcinoma (PDAC) cell lines in combination with the MEK inhibitor trametinib and KRAS inhibitors for 48h led to significant antitumor effects by suppressing ERK and STAT3 phosphorylation and significantly diminishing AKT phosphorylation^[4].

In vivo, TG101348 (60mg/kg) in 200μL volume administrated into mouse models of hemophagocytic lymphohistiocytosis (HLH) via oral gavage twice daily from days 4 to 8 or days 4 through 29 after LCMV infection. TG101348 treatment showed no survival benefit, but improved anemia and thrombocytopenia by inhibiting IFN-γ signaling and modulating G-CSF effects^[5]. TG101348 was given to high-fat high-cholesterol Western diet (WD)–fed Apoe^−/− mice orally via gavage at 120mg/kg/day for the first week and then by 240mg/kg/day for the remaining 9 weeks. TG101348 significantly reduced neutrophilia and monocytosis, reduced atherosclerotic lesion area by about 74% in the aorta, and suppressed STAT5 and ERK1/2 phosphorylation in bone marrow cells^[6]. TG101348 (5mg/kg body weight) was injected (i.p.) into ischemia-reperfusion (I/R)-AKI mice model 24h once in advance before surgery. TG101348 ameliorated renal tubular cell injury and protected renal function by inhibiting ferroptosis through TRIM21 expression downregulation^[7].

References:
[1] 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.Cancer Cell. 2008 Apr;13(4):311-20.
[2] Coltoff A, Mascarenhas J. Fedratinib in 2025 and beyond: indications and future applications.Blood Adv. 2025 Apr 22;9(8):1907-1915.
[3] Geron I, Abrahamsson A E, Barroga C F, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.Cancer Cell. 2008 Apr;13(4):321-30.
[4] Miyazaki S, Kitazawa M, Nakamura S, et al. Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2.Mol Oncol. 2025 Feb;19(2):377-390.
[5] 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.
[6] Tang Y, Liu W L, Wang W, et al. Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice. Cardiovasc Drugs Ther. 2020 Apr;34(2):145-152.
[7] Sun X L, Huang N, Li P, et al. TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life Sci. 2023 May 15:321:121608.

TG101348 (SAR302503)是一种选择性小分子JAK2抑制剂，IC₅₀值为3nM^[1]。TG101348主要用于治疗骨髓纤维化（MF），目前也正积极研究TG101348在骨髓增生异常/骨髓增殖性肿瘤（MDS/MPN）重叠综合征和慢性中性粒细胞白血病（CNL）中的应用^[2]。

在体外实验中，TG101348（300和600nM）预处理人红系巨核细胞UT7/Epo细胞30分钟，随后用10U/ml促红细胞生成素（EPO）刺激，可强烈抑制JAK2介导的STAT5磷酸化和AKT激活，并显著降低GATA-1 S310磷酸化^[3]。TG101348（250nM、500nM和2μM）与MEK抑制剂trametinib及KRAS抑制剂联合应用于胰腺导管腺癌（PDAC）细胞系48小时，通过抑制ERK和STAT3磷酸化并显著降低AKT磷酸化，产生显著抗肿瘤效应^[4]。

在体内实验中，TG101348（60mg/kg）以200μL体积通过口服灌胃方式给药于噬血细胞性淋巴组织细胞增多症（HLH）小鼠模型，每日两次，从LCMV感染后第4天至第8天或第4天至第29天。TG101348治疗未显示生存获益，但通过抑制IFN-γ信号和调节G-CSF效应，改善了贫血和血小板减少^[5]。TG101348通过口服灌胃给予高脂高胆固醇西方饮食（WD）喂养的Apoe^−/−小鼠，第一周剂量为120mg/kg/day，随后9周为240mg/kg/day。TG101348显著减少中性粒细胞增多症和单核细胞增多症，主动脉动脉粥样硬化病变面积减少约74%，并抑制骨髓细胞中STAT5和ERK1/2的磷酸化^[6]。TG101348（5mg/kg体重）在缺血再灌注（I/R）急性肾损伤（AKI）小鼠模型中于手术前24小时一次性腹腔注射。TG101348通过下调TRIM21表达抑制铁死亡，减轻肾小管细胞损伤并保护肾功能^[7]。