发现强效和选择性的BCL6基导向降解剂 (LDD),BCL6-760
Hunter P Shunatona1, Natalie Holmberg Douglas1, Jayce Rhodes1
1Bristol Myers Squibb, 10300 Campus Point Dr. Suite 100, San Diego, California 92121, United States.
Journal of medicinal chemistry
|October 7, 2025
概括
研究人员发现了BCL6-760,它是一种强大的联体导向降解剂 (LDD),向BCL6. 在临床前模型中,这种分子在减少瘤体积方面表现有前途,提供了一种新的治疗途径.
科学领域:
- 药用化学 医学化学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 在某些淋巴瘤中,BCL6是关键的致癌驱动因素.
- 针对BCL6降解是BCL6驱动癌症的治疗策略.
研究的目的:
- 发现和表征一种强效和选择性的BCL6联体导向降解剂 (LDD).
- 为了评估化合物的体外和体内疗效,BCL6-760.
主要方法:
- 结构-活性关系 (SAR) 研究以优化BCL6降解剂.
- 在体外ADME分析和机制研究 (CRBN调解).
- 在小鼠异种移植模型中的体内药理动力学 (PK),药理动力学 (PD) 和疗效研究.
主要成果:
- 鉴定了BCL6-760,它是一种强大的异基生物功能降解剂,具有氨基胺链接剂和基于因达的CRBN结合部分.
- BCL6-760在体外表现出有利的ADME特性和CRBN介导的降解.
- 在OCI-LY-1异种移植模型中,体内研究显示出良好的口服药理动力学,持续的药理动力学效应,以及显著的瘤体积减少 (> 60%).
结论:
- BCL6-760是一种强效和选择性的BCL6LDD,具有前临床疗效.
- 开发的分子表现出有利的类似药物的特性和清洁的降解概况.
- BCL6-760代表了BCL6驱动的恶性瘤的可行的治疗候选者.
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