CD36-mediated endocytosis of proteolysis-targeting chimeras PMID: 40250420

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
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: [email protected].
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: [email protected].

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.