调控诱导接近靶向嵌合体--RIPTACs--用于癌症选择性疗法的异功能小分子策略

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Chemical Biology Pub Date : 2024-08-15 DOI:10.1016/j.chembiol.2024.07.005
Kanak Raina , Chris D. Forbes , Rebecca Stronk , Jonathan P. Rappi Jr. , Kyle J. Eastman , Nilesh Zaware , Xinheng Yu , Hao Li , Amit Bhardwaj , Samuel W. Gerritz , Mia Forgione , Abigail Hundt , Madeline P. King , Zoe M. Posner , Allison D. Correia , Andrew McGovern , David E. Puleo , Rebekka Chenard , James J. Mousseau , J. Ignacio Vergara , Craig M. Crews
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引用次数: 0

摘要

我们描述了一种称为 "调控诱导接近性靶向嵌合体 "或 "RIPTACs "的蛋白质接近性诱导治疗模式:异功能小分子能在肿瘤细胞中选择性表达的靶蛋白(TP)与细胞存活所必需的泛表达蛋白之间产生稳定的三元复合物。由此产生的蛋白-蛋白相互作用(PPI)会削弱必需蛋白的功能,从而导致表达 TP 的细胞选择性死亡。这种方法利用细胞内不同表达的蛋白质作为新型癌症靶点,其优点是不要求靶点是疾病的驱动因素。在这项化学生物学研究中,我们设计的 RIPTACs 含有针对模型 TP 的配体,该配体通过连接体与 JQ1(BRD4)或 BI2536(PLK1)等效应配体或 TMX3013 或 dinaciclib 等 CDK 抑制剂相连。RIPTACs 可选择性地在表达 HaloTag-FKBP 靶点的细胞中聚集,形成协同作用的细胞内三元复合物,并诱导靶点表达细胞产生抗增殖反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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