靶向蛋白水解嵌合体CD36介导的内吞作用，这一成果由美国德克萨斯大学Li Hong-Yu研究团队经过不懈努力而取得。相关论文于2025年4月17日发表于国际顶尖学术期刊《细胞》杂志上。

基于生物素化化学探针的靶标捕捞和基因敲低/敲入方法，课题组发现分化膜细胞36 （CD36）结合并促进多种PROTACs（如SIM1-Me、MZ1和临床ARV-110）和大分子和/或极性小分子药物(如rapalink-1、雷帕霉素、navitoclax、birinapant、tubacin、和阿霉素)，通过cd36介导的早期内体抗原1 (EEA1)/ Ras相关蛋白5A （Rab5）内体级联在体外和/或体内进行。然后，该课题组设计了一种新的化学内吞药物化学策略，通过前药方法改善PROTAC与CD36主题结构修饰的结合，通过自发增加渗透性和溶解度显着提高PROTAC的抗肿瘤功效。

研究人员表示，被动扩散并不能解释为什么许多药物太大和/或太极性而无法打破常规的膜穿透，例如靶向蛋白水解的嵌合体（PROTACs），通常具有一个分子量。800 Da)。

附：英文原文

Title: CD36-mediated endocytosis of proteolysis-targeting chimeras

Author: Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, Jungang Chen, Dongwen Lv, Minmin Wang, Phuc Tran, Tsigereda Weldemichael, Wei Yan, Hongfei Zhou, Gloria M. Martinez, Jingwei Shao, Che-Chia Hsu, Robert Hromas, Daohong Zhou, Zhiqiang Qin, Hui-Kuan Lin, Hong-Yu Li

Issue&Volume: 2025-04-17

Abstract: Passive diffusion does not explain why many drugs are too large and/or too polar for rule-breaking membrane penetration, such as proteolysis-targeting chimeras (PROTACs, generally of a molecular weight > 800 Da). Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility.

DOI: 10.1016/j.cell.2025.03.036

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00386-1