CD36-mediated endocytosis of proteolysis-targeting chimeras

IF 42.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2025-04-17 DOI:10.1016/j.cell.2025.03.036

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

{"title":"CD36-mediated endocytosis of proteolysis-targeting chimeras","authors":"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","doi":"10.1016/j.cell.2025.03.036","DOIUrl":null,"url":null,"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 <em>in vitro</em> and/or <em>in vivo</em>. 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.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":42.5000,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2025.03.036","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

靶向蛋白水解嵌合体cd36介导的内吞作用

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渗透，例如靶向蛋白水解的嵌合体（PROTACs），通常具有一个分子量；800 Da)。在这里，我们使用基于生物素化化学探针的靶标捕捞和基因敲低/敲入方法，我们发现膜分化簇36 （CD36）结合并促进多种PROTACs（例如SIM1-Me， MZ1和临床ARV-110）和大分子和/或极性小分子药物（例如rapallink -1，雷帕霉素，navitoclax, birinapant, tubacin）的摄取和疗效。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，我们设计了一种新的化学内吞药物化学策略，通过前药方法通过结构修饰来改善PROTAC与CD36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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.