评估用于开发口服生物可用的PROTACs的大脑指导弹头的评估
Marisa Actis1, Joel Cresser-Brown2, Elizabeth A Caine3
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Journal of medicinal chemistry
|January 15, 2025
概括
优化蛋白质分解向化马体 (PROTACs) 进行口服是非常具有挑战性的. 这项研究通过修改弹头开发了一种口服生物可用的BET PROTAC (SJ44236),改善了药物开发前景.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 化学生物学 化学生物学
背景情况:
- 蛋白质溶解向金马 (PROTACs) 由于其独特的物理化学性质,往往表现出较差的口服生物利用性.
- 以前的基于基胺 (PG) 的BET PROTACs在体外表现出良好的活性,但在体内药理动力学有限.
- 基于thalidomide的类似物对口服药物开发提出了挑战.
研究的目的:
- 为了优化基于PG的BET PROTACs的口服生物利用性.
- 为了发现新的口服生物可用BET PROTACs.
- 为了比较PROTACs与不同CRBN定向弹头的体外和体内疗效.
主要方法:
- 基于结构的药物设计和新型PROTAC类似物的化学合成.
- 在体外评估蛋白质降解和抗增殖活性.
- 在体内药理动力学研究和在相关模型中的疗效评估.
主要成果:
- 发现SJ44236,一种口服生物可利用的BET PROTAC,具有改善的药理动力学特性.
- 在开发口服可用的PROTAC时,证明了基利胺 (PG) 的实用性.
- 对比分析显示,弹头修改对于口服交付优化至关重要.
结论:
- 弹头的选择和修改对于在PROTAC药物开发中实现口服生物可用性至关重要.
- 基于基胺 (PG) 的PROTACs代表了口服治疗药物的有前途的支架.
- 开发的BET PROTAC SJ44236作为进一步研究和潜在的治疗应用的宝贵工具.
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