CD36-mediated endocytosis of proteolysis-targeting chimeras

Affiliations

• 1. Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
• 2. Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27101, USA.
• 3. Department of Pathology and Winthrop P. Rockefeller Cancer Institute, School of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
• 4. Department of Biochemistry and Structural Biology, Center for Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
• 5. Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
• 6. Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
• 7. Department of Medicine and the Mays Cancer, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
• 8. Department of Pathology and Winthrop P. Rockefeller Cancer Institute, School of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
• 9. Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27101, USA.
• 10. Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

PMID: 40250420    DOI: 10.1016/j.cell.2025.03.036

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.

摘要：被动扩散不能解释为什么许多药物对于破坏规则的膜穿透来说过于大和/或过于极性，例如蛋白水解靶向嵌合体(PROTACs,通常分子量>800Da)。在这里，使用基于生物素化化学探针的靶向捕获和遗传敲低/敲除方法，我们发现分化36(CD36)的膜分簇通过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/或体内结合并促进不同PROTACs(例如SIM1-Me、MZ1和临床ARV-110)和大型和/或极性小分子药物(例如雷帕霉素-1、雷帕霉素、纳威托昔、比里纳潘、图巴欣和阿霉素)的摄取和功效。然后，我们设计了一种新的化学内吞药物化学策略，通过前药方法使用结构修饰改善PROTACs与CD36的结合，通过自发增加通透性和溶解度显著提高PROTAC的抗肿瘤功效。

Keywords: ADME; CD36; ERO5 and BRO5 molecules; PROTAC; cellular uptake; chemical endocytic medicinal chemistry; endocytosis; polar and large molecules; precision medicine; proximity-induced molecules.

关键词: 药代动力学(ADME); 人类白细胞分化抗原36(CD36); ERO5和BRO5分子; 白降解靶向嵌合体(PROTAC)；细胞摄取；化学内吞药物化学；内吞；极性和大分子；精准医学；近端诱导分子，兔单抗，，佰乐博，佰乐博生物