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MD-4251:一流的口服MDM2降解剂,可诱导单剂量治疗的完整瘤回归

Ranjan Kumar Acharyya¹, Liyue Huang¹, Angelo Aguilar¹

¹Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.

Journal of medicinal chemistry

|June 13, 2025

概括

研究人员使用PROTAC技术开发了MD-4251,一种针对MDM2 (一种促进癌症的蛋白质) 的新型口服药物. 这种药物有效降解MDM2,激活p53,并显示出治疗急性白血病的前景.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

MDM2是瘤抑制剂p53.3的关键负调节剂.
在各种癌症中,MDM2是重要的治疗点.
针对MDM2提供了癌症治疗的潜在策略.

研究的目的:

报告MD-4251的发现和特征,一种新的口服有效的MDM2降解剂.
在临床前癌症模型中评估MD-4251的疗效.
评估MD-4251的类似药物的特性,用于治疗开发.

主要方法:

开发MD-4251使用蛋白质溶解向奇美拉 (PROTAC) 技术.
在癌症细胞系中MDM2降解和p53激活的体外评估.
在小鼠模型中的体内研究,以评估药理动力学,药理动力学和抗瘤疗效.
对p53突变细胞系的选择性分析和对药物负债的评估.

主要成果:

MD-4251在RS4;11细胞中显示出强大且快速的MDM2降解 (DC50 = 0.2nM) 和强大的p53激活.
该化合物选择性地抑制了急性白血病细胞系与野生类型p53.3的生长.
在小鼠中,MD-4251表现出极好的口服生物可用性,良好的代谢稳定性,没有显著的CYP或hERG负债.
单次口服剂量导致持续的MDM2耗尽和完整的瘤回归 in vivo.

结论:

MD-4251是使用PROTAC技术开发的第一个口服有效的MDM2降解剂.
MD-4251有效地消耗MDM2,激活p53,并表现出强大的抗白血病活性.
MD-4251代表了癌症治疗的有希望的治疗候选者,特别是在MDM2依赖的恶性瘤中.

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