Meyer Samantha M, Kovachka Sandra, Wang Tenghui, Cameron Michael D, Childs-Disney Jessica L, Disney Matthew D
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, 130 Scripps Way, Jupiter, Florida 33458, United States.
The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States.
J Med Chem. 2025 Jun 26;68(12):12881-12903. doi: 10.1021/acs.jmedchem.5c00749. Epub 2025 Jun 4.
A ribonuclease-targeting chimera (RiboTAC) is a heterobifunctional compound that binds to an RNA target and recruits a ribonuclease to cleave the bound RNA. This study investigates the impact of linker length and composition on RiboTAC potency in leukemia and breast cancer cellular models. Increasing linker length from two polyethylene glycol units to eight increased RiboTAC potency, while longer linker lengths decreased potency. The optimized RiboTAC reduced the abundance of oncogenic transcripts in THP-1 leukemia cells (∼95%) and in MDA-MB-231 triple negative breast cancer cells (∼70%), leading to a subsequent decrease of galectin-1 protein and induction of apoptosis. A series of target engagement assays were developed to validate effector protein-small molecule engagement and in cells, demonstrating the broad potential of these assays to study recruitment of other effector proteins. Collectively, these findings underscore the importance of linker optimization for enhancing RiboTAC potency.
核糖核酸酶靶向嵌合体（RiboTAC）是一种异双功能化合物，它能与RNA靶点结合，并招募核糖核酸酶来切割结合的RNA。本研究在白血病和乳腺癌细胞模型中研究了连接子长度和组成对RiboTAC效力的影响。将连接子长度从两个聚乙二醇单元增加到八个会提高RiboTAC的效力，而更长的连接子长度则会降低效力。优化后的RiboTAC降低了THP-1白血病细胞（约95%）和MDA-MB-231三阴性乳腺癌细胞（约70%）中致癌转录本的丰度，导致半乳糖凝集素-1蛋白随后减少并诱导细胞凋亡。开发了一系列靶点结合测定法来验证效应蛋白与小分子的结合以及在细胞中的结合，证明了这些测定法在研究其他效应蛋白招募方面的广泛潜力。总的来说，这些发现强调了连接子优化对提高RiboTAC效力的重要性。
