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开发基于的新型疏水标签 (SiHyT) 用于向蛋白质降解

Lan Ma¹, Kun Zhang¹, Ziqi Huang¹

¹The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.

Journal of medicinal chemistry

|December 2, 2024

概括

研究人员开发了基于的新型疏水标签 (SiHyT),用于向蛋白质降解. 这些新化合物有效降解突变EGFR,并提供更好的口服生物可用性,促进药物发现.

科学领域:

药用化学医学化学
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:

向蛋白降解 (TPD) 是小分子药物发现的一个快速发展的领域.
疏水标记 (HyT) 策略,特别是基于碳的标签,对蛋白质降解是有效的.
需要新的HyT策略来扩大TPD工具箱.

研究的目的:

引入一种新的基于的疏水标签 (SiHyT) 类别,用于向蛋白质降解.
评估SiHyT化合物的有效性,特别是那些将Gefitinib与基于的标签结合在一起的化合物,用于降解突变EGFR.
探索SiHyT战略在开发PD-L1和BTK等其他目标的降解剂方面的潜力.

主要方法:

新型Gefitinib-SiHyT结合物的合成和表征.
在体外和体内评估通过ubiquitin-proteasome系统 (UPS) 对降解剂7对突变EGFR的疗效.
评估降解剂7的代谢稳定性和口服生物可用性.
涉及EGFR-HSP90复杂解离和E3酶招募的机制研究 (RNF149).
应用SiHyT策略来发现PD-L1和BTK降解剂.

主要成果:

降解剂7,Gefitinib-SiHyT结合物,通过UPS在体外和体内有效降解突变EGFRs.
与碳基HyTs相比,Degrader 7表现出增强的口服生物可用性和优越的代谢稳定性.
降解剂7通过解离EGFR-HSP90复合体和招募E3结合酶RNF149.9来起作用.
SiHyT策略成功地产生了PD-L1和BTK的强效和选择性降解剂.

结论:

基于的疏水标签 (SiHyT) 代表了针对蛋白质降解的新有效策略.
SiHyT化合物在代谢稳定性和口服生物利用性方面具有优势,这对于药物开发至关重要.
SiHyT方法在扩大TPD药物范围和设计未来治疗方法方面具有显著的前景.

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