CD36-mediated endocytosis of proteolysis-targeting chimeras

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

CD36-mediated endocytosis of proteolysis-targeting chimeras

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

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3219-3237.e18
Journal	Cell
Volume	188
Issue number	12
DOIs	https://doi.org/10.1016/j.cell.2025.03.036
State	Published - Jun 12 2025

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2025.03.036

Cite this

@article{46032936e2f14ab39140f32cf6d6d173,

title = "CD36-mediated endocytosis of proteolysis-targeting chimeras",

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",

author = "Zhengyu Wang and Pan, \{Bo Syong\} and Manne, \{Rajesh Kumar\} and Jungang Chen and Dongwen Lv and Minmin Wang and Phuc Tran and Tsigereda Weldemichael and Wei Yan and Hongfei Zhou and Martinez, \{Gloria M.\} and Jingwei Shao and Hsu, \{Che Chia\} and Robert Hromas and Daohong Zhou and Zhiqiang Qin and Lin, \{Hui Kuan\} and Li, \{Hong Yu\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = jun,

day = "12",

doi = "10.1016/j.cell.2025.03.036",

language = "English (US)",

volume = "188",

pages = "3219--3237.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "12",

}

TY - JOUR

T1 - CD36-mediated endocytosis of proteolysis-targeting chimeras

AU - Wang, Zhengyu

AU - Pan, Bo Syong

AU - Manne, Rajesh Kumar

AU - Chen, Jungang

AU - Lv, Dongwen

AU - Wang, Minmin

AU - Tran, Phuc

AU - Weldemichael, Tsigereda

AU - Yan, Wei

AU - Zhou, Hongfei

AU - Martinez, Gloria M.

AU - Shao, Jingwei

AU - Hsu, Che Chia

AU - Hromas, Robert

AU - Zhou, Daohong

AU - Qin, Zhiqiang

AU - Lin, Hui Kuan

AU - Li, Hong Yu

PY - 2025/6/12

Y1 - 2025/6/12

N2 - 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.

AB - 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.

KW - ADME

KW - CD36

KW - ERO5 and BRO5 molecules

KW - PROTAC

KW - cellular uptake

KW - chemical endocytic medicinal chemistry

KW - endocytosis

KW - polar and large molecules

KW - precision medicine

KW - proximity-induced molecules

UR - https://www.scopus.com/pages/publications/105003260223

UR - https://www.scopus.com/pages/publications/105003260223#tab=citedBy

U2 - 10.1016/j.cell.2025.03.036

DO - 10.1016/j.cell.2025.03.036

M3 - Article

C2 - 40250420

AN - SCOPUS:105003260223

SN - 0092-8674

VL - 188

SP - 3219-3237.e18

JO - Cell

JF - Cell

IS - 12

ER -

CD36-mediated endocytosis of proteolysis-targeting chimeras

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this