在临床前模型中,小分子共同准CKIα和转录基因酶CDK7/9控制AML
Waleed Minzel1, Avanthika Venkatachalam1, Avner Fink1
1The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cell
|August 28, 2018
概括
新的向素激酶Iα (CKIα),CDK7和CDK9的抑制剂通过向超级增强剂来激活p53并抑制白血病. 这些药物有望治疗急性髓性白血病 (AML),同时保持正常的血细胞发育.
科学领域:
- 癌症学
- 分子生物学
- 药物开发
背景情况:
- 凯酶Iα (CKIα) 除激活了p53,而其降解是莱纳利多米德在白血病前期有效性的关键.
- 急性髓性白血病 (AML) 是由由超增强剂 (SE) 调节的瘤基因驱动的.
研究的目的:
- 为增强抗白血病活性开发针对CKIα,CDK7和CDK9的新型抑制剂.
- 研究这些抑制剂对AML的SE和p53激活的作用机制.
主要方法:
- 开发针对CKIα和转录激酶CDK7/ 9的双抑制剂.
- 在小鼠初级AML细胞和患者衍生的异种移植中分析SE.
- 对p53稳定,基因转录抑制和亡诱导的评估.
- 在AML小鼠模型和异种移植中评估治疗疗效.
主要成果:
- 开发的抑制剂共同向CKIα,CDK7和CDK9,增加了p53的激活.
- 抑制剂在AML细胞中消除新获得的SE,并抑制SE驱动的瘤基因转录.
- 联合抑制可以协同稳定p53,诱导细胞亡,并选择性地消除白血病原体.
- 在多种AML模型中证明治疗效果,包括MLL- AF9和患者衍生的异种移植.
结论:
- 双CKIα/CDK7/9抑制是一种有前途的AML治疗策略.
- 这些抑制剂通过破坏SE驱动的瘤基因成来选择性地向白血病细胞.
- 这种方法提供了治疗白血病的潜力.
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