JMC14:一种新的双PI3Kδ/CSF1R抑制剂,在血液和固体瘤中具有强大的抗瘤活性
1Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Acta pharmacologica Sinica
|May 19, 2025
概括
一种新型的双重抑制剂JMC14有效向PI3Kδ和CSF1R,在血液癌症和三阴性乳腺癌等固体瘤中表现出强大的抗癌活性.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 在B细胞恶性瘤中,酸酸3-激酶三角酶 (PI3Kδ) 失调.
- 殖民地刺激因子1受体 (CSF1R) 调节固体瘤中的瘤相关巨细胞 (TAMs).
- 现有的PI3Kδ或CSF1R抑制剂在临床应用方面存在局限性,包括毒性和疗效.
研究的目的:
- 确定和描述JMC14,一种新的PI3Kδ和CSF1R双重抑制剂.
- 在血液和固体恶性瘤的临床前模型中评估JMC14的疗效.
- 研究JMC14在调节瘤免疫微环境中的作用机制.
主要方法:
- 综合和JMC14的结构特征.
- 在体外激酶试验测试以确定PI3Kδ和CSF1R的IC50值.
- 使用扩散性大B细胞淋巴瘤 (DLBCL) 细胞系进行抗增殖试验.
- 使用DLBCL异种移植和小鼠三阴性乳腺癌 (TNBC) 模型的体内研究.
- 流细胞计和免疫组织化学检查,以评估免疫细胞透和TAM极化.
主要成果:
- 在JMC14中,PI3Kδ (IC50=12nM) 和CSF1R (IC50=143nM) 具有强烈的抑制,具有良好的选择性.
- JMC14对DLBCL细胞系表现出强大的抗增殖活性,表现优于idelalisib.
- 在体内研究表明,在DLBCL异种移植中,瘤进展的剂量依赖性抑制和在TNBC模型中具有强大的抗瘤活性.
- JMC14通过减少M2类TAM和增强CD8+T细胞透来重塑TNBC中的免疫微环境.
结论:
- JMC14是一种强大的双PI3Kδ/CSF1R抑制剂,在血液和固体瘤中具有显著的临床前疗效.
- JMC14显示出治疗PI3Kδ和/或CSF1R过度激活的恶性瘤的潜力.
- JMC14可能成为研究PI3Kδ,CSF1R,瘤进展和免疫重编程之间的相互作用的宝贵工具.
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