JAK1-IN-3

JAK1-IN-3, is a highly selective, orally active Janus kinase 1 (JAK1) inhibitor with an IC₅₀ value of 73nM^[1-3]. JAK1-IN-3 has an IC₅₀>14.7µM for JAK2^[1]. JAK1-IN-3 suppresses the activation of Signal Transducer and Activator of Transcription 3 (STAT3) by inhibiting the phosphorylation of tyrosine by JAK^[4]. JAK1-IN-3 can also inhibit tumor growth and demonstrates favorable drug metabolism and pharmacokinetic (DMPK) properties^{[2, 5]}.

In vitro, H1975 cells were treated with Osimertinib (250nM), JAK1-IN-3 (5µM), or both for 48 hours. The combination treatment of JAK1-IN-3 and Osimertinib significantly enhanced the inhibitory effect on cell growth compared with monotherapy^[6].

In vivo, in female NCr nude mice bearing tumors, the combination treatment with JAK1-IN-3 (50mg/kg) and Osimertinib (2.5mg/kg) via oral administration showed greater tumor growth inhibition than either JAK1-IN-3 or Osimertinib alone^[2].

References:
[1] Annika Birgitta Margareta ÅSTRAND, et al. Compounds and methods for inhibiting jak. WO2017050938A1.
[2] Su Q, Banks E, Bebernitz G, et al. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor. J Med Chem. 2020;63(9):4517-4527.
[3] Song Y, Malpica L, Cai Q, et al. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study. Lancet Oncol. 2024;25(1):117-125.
[4] Edirisinghe DT, Kaur J, Lee YQ, et al. The role of the tumour microenvironment in lung cancer and its therapeutic implications. Med Oncol. 2025;42(6):219. Published 2025 May 23.
[5] Qureshy Z, Johnson DE, Grandis JR. Targeting the JAK/STAT pathway in solid tumors. J Cancer Metastasis Treat. 2020;6:27.
[6] Kim Y, Jeon E, Ahn H, Kang J, Sim T. Identification of Thieno[3,2-d]pyrimidine derivatives as potent and selective Janus Kinase 1 inhibitors. Eur J Med Chem. 2025;286:117308.

JAK1-IN-3是一种高选择性、口服活性的Janus激酶1（JAK1）抑制剂，IC₅₀值为73nM^[1-3]。JAK1-IN-3对JAK2的IC₅₀>14.7µM^[1]。JAK1-IN-3通过抑制JAK介导的酪氨酸磷酸化，抑制信号转导及转录激活因子3（STAT3）的激活^[4]。JAK1-IN-3还能够抑制肿瘤生长，并表现出良好的药物代谢和药代动力学（DMPK）特性^{[2, 5]}。

在体外，H1975细胞分别用奥希替尼（250nM）、JAK1-IN-3（5µM）或两者联合处理48小时。与单独治疗相比，JAK1-IN-3与奥希替尼的联合治疗显著增强了对细胞生长的抑制效果^[6]。

在体内，对携带肿瘤的雌性NCr裸鼠使用JAK1-IN-3（50mg/kg）和奥希替尼（2.5mg/kg）联合口服给药，联合治疗比单独使用JAK1-IN-3或奥希替尼显示出更强的肿瘤生长抑制效果^[2]。