Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis,Journal of Medicinal Chemistry

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Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-24 , DOI: 10.1021/acs.jmedchem.4c00949
Shang Li ₁ , Liangliang Ma ₁ , Xinxin Li ₁ , Yuhan Jiang ₁ , Zhongwen Luo ₁ , Fucheng Yin ₁ , Yonglei Zhang ₁ , Yifan Chen ₁ , Siyuan Wan ₁ , Han Zhou ₁ , Lingyi Kong ₁ , Xiaobing Wang ₁

Affiliation

Mixed lineage kinase domain–like pseudokinase (MLKL) initiates necroptosis and could serve as a therapeutic target related to a series of human diseases. Proteolysis-targeting chimeras (PROTACs) are useful tools for degrading pathological proteins and blocking disease processes. Using computer-aided modeling and molecular dynamics simulations, we developed a series of covalent MLKL PROTACs by linking and optimizing a theophylline derivative that covalently targets MLKL. Via structure–activity relationship studies, MP-11 was identified as a potent MLKL PROTAC degrader. Furthermore, MP-11 showed lower toxicity than the original MLKL ligand, exhibiting nanomolar-scale antinecroptotic activity on human cell lines. Xenograft model studies showed that MP-11 effectively degraded MLKL in vivo. Importantly, our study demonstrates that the covalent binding strategy is an effective approach for designing MLKL-targeting PROTACs, serving as a model for developing PROTACs to treat future necroptosis-related human diseases.

中文翻译：

通过优化茶碱衍生物配体发现共价 MLKL PROTAC 降解剂用于治疗坏死性凋亡

混合谱系激酶结构域样假激酶（MLKL）可引发坏死性凋亡，可作为与一系列人类疾病相关的治疗靶点。蛋白水解靶向嵌合体 (PROTAC) 是降解病理蛋白和阻断疾病进程的有用工具。利用计算机辅助建模和分子动力学模拟，我们通过连接和优化共价靶向 MLKL 的茶碱衍生物，开发了一系列共价 MLKL PROTAC。通过结构-活性关系研究， MP-11被鉴定为有效的 MLKL PROTAC 降解剂。此外， MP-11显示出比原始 MLKL 配体更低的毒性，对人类细胞系表现出纳摩尔级的抗坏死活性。异种移植模型研究表明MP-11在体内有效降解 MLKL。重要的是，我们的研究表明，共价结合策略是设计靶向 MLKL 的 PROTAC 的有效方法，可作为开发 PROTAC 治疗未来坏死性凋亡相关人类疾病的模型。

更新日期：2024-08-24

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