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合理设计的仿制PI3K-BET代体抑制剂在MYC驱动的淋巴瘤中引起治疗反应

Danielle H Oh^1,2,3, Xiao Ma^4,5, Simon J Hogg^3,6

¹Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne VIC 3168, Australia.

Proceedings of the National Academy of Sciences of the United States of America

|August 29, 2023

概括

针对酸氨基醇-3-激酶 (PI3K) 和体和外端体 (BET) 的双重抑制剂对淋巴瘤表现出协同作用. 这种综合方法提供了一个有前途的战略,通过克服耐药机制来持续控制疾病.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

酸丁醇-3-酶 (PI3K) 单剂抑制剂和体和外端体 (BET) 体在具有c-MYC失调的淋巴瘤中表现出有限的疗效.
补偿性表观遗传和信号网络有助于抵抗单剂疗法.
需要结合的抑制策略来克服这些抵抗机制.

研究的目的:

在机械和治疗上验证合理设计的双PI3K/BET代蛋白抑制剂.
在临床前淋巴瘤模型中评估PI3K和BET联合抑制的疗效.
探索MYC驱动淋巴瘤的新型治疗策略.

主要方法:

设计和合成连接PI3K和BET抑制剂药的仿真小分子.
在体外对选择性和细胞功能的评估 (纳米级范围).
在侵袭性Eμ-Myc淋巴瘤模型中的体内疗效研究.

主要成果:

领先的双重抑制剂候选者表现出高选择性和强大的细胞活性.
观察到令人信服的体内疗效,包括在侵袭性淋巴瘤模型中的治愈反应.
联合抑制策略显示出协同作用的抗癌活性.

结论:

联合PI3K和BET抑制是淋巴瘤治疗的治疗上可行的策略.
优化的嵌合式小分子技术为正交MYC对抗提供了一种新的方法.
这些发现支持c-MYC失调淋巴瘤治疗的潜在转变.

关键词:

在BET-类域内.cMYCC 这是一个很好的例子.奇幻的小分子小分子.酸氨基醇-3-酶

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