Pharmacological profiling of a berbamine derivative for lymphoma treatment. Pharmacological profiling of a berbamine derivative for lymphoma treatment

Ca2+/calmodulin-dependent protein kinase II gamma (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of Berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared to BBM, PA4 showed improved potency and specificity, and was more cytotoxic against lymphoma and leukemia compared to other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased ROS production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma (TCL) mouse model. Pharmacokinetics studies depicted quick absorption into plasma after oral administration with a max concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hr. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma. Overall design: To determine the underlying mechanisms of PA4-induced cell death, we compared the global gene profiles between vehicle control (DMSO) and 1 µM PA4 treatment in H9 cells

Ca2+/钙调蛋白依赖性蛋白激酶IIγ（Ca2+/calmodulin-dependent protein kinase II gamma, CAMKIIγ）已被鉴定为癌症治疗的潜在靶点。基于本团队此前关于小檗胺（Berbamine, BBM）作为CAMKIIγ抑制剂的研究，我们合成了一种新型BBM衍生物，命名为PA4。与BBM相比，PA4的活性与特异性均得到显著提升，且相较于其他癌症类型，其对淋巴瘤与白血病的细胞毒性更强。除可间接调控c-Myc蛋白稳定性外，本研究还证实，PA4的细胞毒性效应亦可通过增强淋巴瘤细胞内活性氧（ROS）生成所介导。PA4可在异种移植T细胞淋巴瘤（T-cell lymphoma, TCL小鼠模型中显著抑制体内肿瘤生长。药代动力学研究显示，PA4经口给药后可快速吸收入血浆，于5.33 ± 2.31小时达到血浆峰浓度1680 ± 479 ng/mL。经计算，其口服绝对生物利用度为34.1%。PA4的毒性评估结果表明，本实验中采用的治疗窗口安全性良好，可支持后续开发。鉴于PA4的有效性、安全性及良好的药代动力学特性，其为治疗淋巴瘤的潜在候选先导化合物。总体实验设计：为阐明PA4诱导细胞死亡的潜在机制，我们对载体对照（二甲基亚砜，DMSO）与1 µM PA4处理H9细胞后的全基因表达谱进行了对比分析。