2. Academic Validation
  3. CD36-mediated endocytosis of proteolysis-targeting chimeras

CD36-mediated endocytosis of proteolysis-targeting chimeras

  • Cell. 2025 Jun 12;188(12):3219-3237.e18. doi: 10.1016/j.cell.2025.03.036.
Zhengyu Wang 1,  Bo-Syong Pan 2,  Rajesh Kumar Manne 2,  Jungang Chen 3,  Dongwen Lv 4,  Minmin Wang 5,  Phuc Tran 6,  Tsigereda Weldemichael 6,  Wei Yan 1,  Hongfei Zhou 5,  Gloria M Martinez 5,  Jingwei Shao 6,  Che-Chia Hsu 2,  Robert Hromas 7,  Daohong Zhou 4,  Zhiqiang Qin 8,  Hui-Kuan Lin 9,  Hong-Yu Li 10
Affiliations

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. Electronic address: zqin@uams.edu.
  • 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. Electronic address: hui-kuan.lin@duke.edu.
  • 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. Electronic address: lih1@uthscsa.edu.
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.

Keywords

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

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