催化抑制p300优先准IRF4瘤活性和瘤生长在多发性髓瘤
W Frank Lenoir1, Michael R McKeown1, Giulia Giorgetti2
1Kronos Bio, Cambridge, MA, United States.
Cancer research
|November 17, 2025
概括
研究人员确定p300是多发性骨髓瘤 (MM) 中瘤转录因子IRF4的关键合作伙伴. 抑制p300 (一种KAT酶) 有效地向MM细胞,显示出新的MM疗法的前景.
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:
- 转录因子IRF4对于多发性骨髓瘤 (MM) 存活至关重要,但仍未使用药物.
- 确定IRF4的关键合作伙伴对于开发有针对性的MM疗法至关重要.
研究的目的:
- 使用转录监管网络 (TRN) 映射识别IRF4合作伙伴.
- 评估p300/CBP氨酸转化酶 (KAT) 抑制剂作为MM的治疗策略.
主要方法:
- 使用了转录调节网络 (TRN) 映射和定量互动组映射.
- 开发和测试了p300/CBP KAT抑制剂,以检测它们抑制IRF4活性和MM扩散的能力.
- 进行了与现有的p300/CBP代胺抑制剂进行比较分析.
主要成果:
- p300被确定为一个关键的IRF4合作伙伴,IRF4是一个非常丰富的MM特异性依赖.
- p300/CBP KAT抑制有效抑制了IRF4活性和MM细胞增殖,无论是体外还是体内.
- 与odomain 抑制剂相比,KAT 抑制剂显示出对MM细胞的优先向和对IRF4的优异抑制.
- 与KAT抑制剂和其他MM疗法的联合治疗显示出协同作用的抗瘤效应.
结论:
- p300是MM中IRF4的关键联合激活剂,使其成为一个可行的治疗点.
- p300/CBP KAT抑制是MM治疗的有希望的策略,特别是在组合疗法中.
- 对于MM,正在进行的p300/CBP KAT抑制剂的临床开发是合理的.
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