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基于结构的新口服生物可用BRD9-PROTACs的鉴定,用于治疗急性髓细胞白血病

Jingyu Zhang¹, Haiting Duan¹, Renzhao Gui²

¹Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.

European journal of medicinal chemistry

|November 4, 2024

概括

一种新的口服BRD9 PROTAC,C6,在急性髓性白血病 (AML) 细胞中有效降解BRD9. 由于其有效性和有利的药理动力学特性,C6在AML治疗中显示出显著的治疗潜力.

科学领域:

生物化学生物化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

BRD9对于基因转录和染色质重塑至关重要,影响急性髓性白血病 (AML) 细胞存活率.
现有的BRD9抑制剂和PROTAC在AML治疗中的有效性,选择性和药物可用性方面面临挑战.

研究的目的:

开发和描述一种新的,口服活性的BRD9 PROTAC (C6) 用于AML治疗.
在AML模型中评估C6的降解效率,选择性和治疗潜力.

主要方法:

开发一种口服活跃的BRD9 PROTAC (C6),使用高效的E3结合酶.
使用生物化学测定 (DC50值) 评估BRD9降解效率和选择性.
针对AML细胞系 (MV4-11) 的C6活性体外评估和药理动力学概况 (Cmax).

主要成果:

C6证明了强大和选择性的BRD9降解,DC50为1.02±0.52nM,而不会影响BRD4或BRD7.
在实验室中,C6对MV4-11AML细胞系表现出显著的疗效.
C6表现出良好的口服生物利用性,其Cmax为3436.95 ng/mL.

结论:

C6是一种新的BRD9 PROTAC,具有出色的降解特性和口服活性.
C6表明作为治疗急性髓性白血病的潜在治疗剂具有前途.
进一步开发C6可以克服目前在AML中的BRD9向策略的局限性.

关键词:

急性骨髓性白血病 (AML) 是一种急性骨髓性白血病.含有基多马因的蛋白质9 停靠的对接方式通过口服进行生物可用性.针对蛋白质溶解的木乃伊.

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