CD36-mediated endocytosis of proteolysis-targeting chimeras

Zhengyu Wang¹, Bo-Syong Pan², Rajesh Kumar Manne², Jungang Chen³, Dongwen Lv⁴, Minmin Wang⁵, Phuc Tran⁶, Tsigereda Weldemichael⁶, Wei Yan¹, Hongfei Zhou⁵, Gloria M Martinez⁵, Jingwei Shao⁶, Che-Chia Hsu², Robert Hromas⁷, Daohong Zhou⁴, Zhiqiang Qin⁸, Hui-Kuan Lin⁹, Hong-Yu Li¹⁰

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
PMCID: PMC12167158 (available on 2026-06-12)
DOI: 10.1016/j.cell.2025.03.036

CD36-mediated endocytosis of proteolysis-targeting chimeras

Zhengyu Wang et al. Cell. 2025.

. 2025 Jun 12;188(12):3219-3237.e18.

doi: 10.1016/j.cell.2025.03.036. Epub 2025 Apr 17.

Authors

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
PMCID: PMC12167158 (available on 2026-06-12)
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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Conflict of interest statement

Declaration of interests H.-Y.L. is a shareholder of Univiatis, LLC and Sirronatx, Inc.; H.-Y.L. and Z.W. have a patent application; and H.-K.L. is a consultant for Stablix, Inc. and Chang Gung University of Science and Technology.

References

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CD36-mediated endocytosis of proteolysis-targeting chimeras

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CD36-mediated endocytosis of proteolysis-targeting chimeras

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Conflict of interest statement

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