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通过在血液性恶性瘤中抑制原蛋白来向EP300/CBP的治疗向

Luciano Nicosia¹, Gary J Spencer¹, Nigel Brooks²

¹Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.

|November 23, 2023

概括

伊诺布罗迪布 (CCS1477),是一种EP300/CBP代蛋白抑制剂,通过破坏增强器网络,有效向血液瘤. 这种药物在急性髓性白血病和多发性髓瘤的临床试验中表现有前途.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

像急性髓性白血病 (AML) 和多发性髓瘤 (MM) 这样的血液恶性瘤是由复杂的遗传改变驱动的.
通过表观遗传修饰来调节的增强器区域在癌症发育中起着至关重要的作用.
EP300和CBP是关键的表观遗传调节剂,通常与癌症有关.

研究的目的:

为了评估CCS1477 (inobrodib) 的疗效,一种选择性的EP300/CBP代蛋白抑制剂.
在血液恶性瘤模型中研究CCS1477的作用机制.
评估CCS1477在复发或耐药AML和MM的临床活性.

主要方法:

使用髓性白血病和髓瘤细胞系的体外研究.
分析EP300/CBP从增强区域的驱逐情况.
评估与分化和瘤发生相关的基因表达变化.
临床前与标准护理药物的体内组合研究.
在患有复发/耐药AML和MM的患者中进行早期临床试验.

主要成果:

在血液恶性瘤模型中,CCS1477诱导细胞循环停止和分化.
该药物促进了AML细胞中MYB占用增强剂的EP300/CBP驱逐,降低了瘤网络的调节.
在髓瘤细胞中,CCS1477从FGFR3中驱逐了EP300/CBP,并将其重新分配到TCF3/E2A位点.
用CCS1477单一治疗显示AML的分化反应和MM患者的客观反应.
临床前研究表明,当CCS1477与标准疗法结合使用时,会产生协同效应.

结论:

CCS1477是一种强大的EP300/CBP代蛋白抑制剂,具有显著的临床前和临床早期活性.
该药物破坏了关键的转录因子占据的增强器网络,从而产生抗癌效应.
CCS1477显示出作为单一疗法和联合疗法治疗AML和MM的前景.

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