斯克里普斯研究所Li Ye团队在研究中取得进展。他们研制了绘制整个哺乳动物体内共价抗癌药物的细胞靶标。该项研究成果发表在2025年12月22日出版的《细胞》上。
通过利用独特的点击反应动力学，课题组研究人员开发了体积清除辅助组织点击化学（vCATCH），以实现跨越三维（3D）哺乳动物身体的深度和均匀的点击标记。通过简单和被动的孵育步骤，vCATCH在整个成人母体中提供细胞分辨率药物成像。该研究组将vCATCH与基于水凝胶的三维成像溶剂清除器官（HYBRiD）成像和虚拟现实相结合，对两种临床癌症药物阿法替尼和伊鲁替尼的体内靶标进行可视化和量化，再现了它们已知的药理分布，并揭示了以前未报道的组织和细胞类型参与可能与脱靶效应相关。vCATCH提供了一个覆盖全身的、无偏见的平台，以前所未有的规模和精度绘制共价药物接合。
据悉，随着他们对生物系统的理解达到单细胞和高空间分辨率，药理学方法与这种精度相匹配以理解药物作用变得势在必行。这种需求对于靶向共价抑制剂来说尤其迫切，这些抑制剂目前正在重新进入癌症治疗的阶段。
附：英文原文
Title: Mapping cellular targets of covalent cancer drugs in the entire mammalian body
Author: Zhengyuan Pang, Verina H. Leung, Cailynn C. Wang, Ahmadreza Attarpour, Anthony Rinaldi, Hanbing Shen, Maria Dolores Moya-Garzon, Logan H. Sigua, Claire Rammel, Alexandra Selke, Christopher Glynn, Melaina Yender, Senhan Xu, Javid J. Moslehi, Peng Wu, Jonathan Z. Long, Maged Goubran, Benjamin F. Cravatt, Li Ye
Issue&Volume: 2025-12-22
Abstract: As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.
DOI: 10.1016/j.cell.2025.11.030
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01365-0