用于治疗急性肺损伤的MyD88靶向分子胶d21的设计、合成和生物学评价
Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury.
摘要(中文译文)
髓样分化因子88（MyD88）是炎症信号传导的关键介质。然而，MyD88抑制剂的开发一直受到限制，且尚无关于MyD88降解剂的报道。基于我们此前鉴定的MyD88抑制剂，并采用模板辅助修饰策略，我们设计并合成了40种新型衍生物，并确定了最优化合物，该化合物可通过促进环指蛋白126（RNF126）（一种E3泛素连接酶）与MyD88之间的相互作用，从而促进MyD88的泛素化及其后续降解，进而抑制核因子κB（NF-κB）通路的激活。亚急性毒性试验表明，该化合物具有良好的安全性。此外，该化合物在盲肠结扎穿刺（CLP）和脂多糖（LPS）诱导的急性肺损伤（ALI）模型中均表现出显著的抗炎作用，有效改善ALI症状。这些发现表明，该化合物作为一种靶向MyD88的分子胶降解剂用于ALI治疗具有相当大的前景。
Abstract
Myeloid differentiation factor 88 (MyD88) is a critical mediator of inflammatory signaling. However, the development of MyD88 inhibitors has been limited, and there are no reports on MyD88 degraders. Based on our previously identified MyD88 inhibitor and employing a template-assisted modification strategy, we designed and synthesized 40 novel derivatives, and identified the optimal compound , which could inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation by facilitating the interaction between ring finger protein 126 (RNF126) (an E3 ubiquitin ligase) and MyD88, thereby promoting ubiquitination and subsequent degradation of MyD88. The subacute toxicity test indicated that had good safety profile. Furthermore, it demonstrated significant anti-inflammatory effects in both cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced acute lung injury (ALI) models, effectively ameliorating ALI symptoms. These findings suggest that holds considerable promise as a MyD88-targeting molecular glue degrader for the treatment of ALI.
如何引用
AMA
Luxiao Zhu, Dan Tang, Ting Chen, Chenhui Sun, Ke Dong, Qi Chen, et al. Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c00755.
APA
Luxiao Zhu, Dan Tang, Ting Chen, Chenhui Sun, Ke Dong, Qi Chen, et al (2026). Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c00755
GB/T 7714
Luxiao Zhu, Dan Tang, Ting Chen, Chenhui Sun, Ke Dong, Qi Chen, et al. Design, Synthesis, and Biological Evaluation of a MyD88-Targeted Molecular Glue d21 for the Treatment of Acute Lung Injury.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c00755.
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