ND-16：一种通过靶向 JAK2 抑制皮肤 T 细胞淋巴瘤生长的新型化合物。
ND-16: A Novel Compound for Inhibiting the Growth of Cutaneous T Cell Lymphoma by Targeting JAK2.
机构信息
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, P.R. China.
Shaanxi Provincial People's Hospital, Xi'an, 710068, P.R. China.
出版信息
Curr Cancer Drug Targets. 2022;22(4):328-339. doi: 10.2174/1568009622666220225121009.
OBJECTIVE
Cutaneous T cell lymphoma (CTCL) is a kind of extranodal non-Hodgkin Tcell lymphoma without healable treatment in the clinic. JAK2 amplification in CTCL patients makes it a potential target for CTCL treatment. In the present study, we aimed to evaluate the anticancer effect of ND-16, a novel nilotinib derivate, on CTCL cells and the underlying mechanism targeting JAK2.
METHODS AND RESULTS
We found that ND-16 was capable of regulating JAK2 and had a selective inhibitory effect on CTCL H9 cells. The surface plasmon resonance and molecular docking study indicated ND-16 bound to JAK2 with a high binding affinity. Further investigation revealed that ND-16 inhibited the downstream cascades of JAK2, including STATs, PI3K/AKT/mTOR, and MAPK pathways, followed by regulation of Bcl-2 family members and cell cycle proteins CDK/- Cyclins. Flow cytometry analysis confirmed these results that ND-16-treated H9 cells showed cell apoptosis and cell cycle arrest at S-phase.
CONCLUSION
ND-16 may be of value in a potential therapy for the management of CTCL.
目的
皮肤 T 细胞淋巴瘤（CTCL）是一种结外非霍奇金 T 细胞淋巴瘤，临床上尚无治愈方法。CTCL 患者存在 JAK2 扩增，使其成为 CTCL 治疗的潜在靶点。本研究旨在评估新型尼罗替尼衍生物 ND-16 对 CTCL 细胞的抗癌作用及其针对 JAK2 的潜在作用机制。
方法与结果
我们发现 ND-16 能够调节 JAK2，并对 CTCL H9 细胞具有选择性抑制作用。表面等离子体共振和分子对接研究表明，ND-16 与 JAK2 具有高结合亲和力。进一步研究表明，ND-16 抑制了 JAK2 的下游级联反应，包括 STATs、PI3K/AKT/mTOR 和 MAPK 通路，随后调节 Bcl-2 家族成员和细胞周期蛋白 CDK/-Cyclins。流式细胞术分析证实，ND-16 处理的 H9 细胞表现出细胞凋亡和 S 期细胞周期停滞。
结论
ND-16 可能对 CTCL 的治疗管理具有价值。
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