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In a nutshell
- Scientists discovered that a protein called CD36 acts as a gateway for large drug molecules to enter cells, potentially allowing IV drugs to be reformulated as oral medications.
- This finding challenges the “Rule of Five” in pharmaceutical development, which limited drug size to under 500 daltons for effective cell entry.
- By modifying drugs to better interact with CD36, researchers enhanced drug uptake and effectiveness up to 16-fold, opening new possibilities for treating brain cancer, Alzheimer’s, and other diseases.
SAN ANTONIO, Texas — Researchers have made a major breakthrough that could transform IV medications into oral treatments for diseases like brain cancer and Alzheimer’s, potentially revolutionizing how we administer complex drugs.
A team led by Hong-Yu Li, PhD, professor of medicinal chemistry and chemical biology at the University of Texas Health Science Center at San Antonio, has identified a protein called CD36 as the main gateway for complex medications to enter cells. The finding, published in Cell, overturns the longstanding belief that large drugs can’t efficiently penetrate cell membranes.
“This innovative chemical approach can potentially make any intravenous drug able to be taken orally,” said Dr. Robert A. Hromas, dean of the School of Medicine at UT Health San Antonio, in a statement. “It also can promote any drug crossing the blood-brain barrier. This will remarkably broaden the number of agents we have to treat brain cancer or dementia.”
Breaking the Rule of Five
For decades, drugmakers followed the so-called “Rule of Five,” which says medications need to be small and fat-soluble to pass through a cell membrane. Based on this rule, big or water-loving molecules were thought to be useless as oral drugs.
Yet many newer medicines violate this principle while maintaining their effectiveness. This includes PROTACs (proteolysis-targeting chimeras) – innovative cancer drugs that tag disease-causing proteins for destruction. They’re much larger than 500 daltons (a unit used to measure molecules), and still manage to work.
“Many drugs are too large and/or too polar for rule-breaking membrane penetration, such as proteolysis-targeting chimeras generally of a molecular weight greater than 800 [Daltons],” the researchers write.
The CD36 Doorway
So how will CD36 help? Instead of slipping through cell membranes, these oversized drugs are actively transported into cells by CD36, a protein sitting on the cell surface. The process is known as endocytosis — basically, the cell “swallows” the drug.
To test this, the researchers created cancer cells with lower levels of CD36. When exposed to several large drugs, these cells absorbed far less of them. In some cases, drug uptake dropped by more than nineteen times.
“This was completely unexpected in the research field,” Li said. “For decades, it was thought that molecules this large couldn’t cross membranes effectively, since the endocytic cellular uptake of chemicals was unknown. Through chemistry and biology, we identified CD36 as a protein for uptake and optimized chemicals better engaging with CD36 to internalize these drugs to more efficiently reach target proteins.”
Engineering Better Medications
Once they knew CD36 was the key, the scientists went a step further: they modified existing drugs to interact more strongly with CD36. This new method — which they call chemical endocytic medicinal chemistry — made the drugs better at getting into cells and more effective at killing cancer cells.
They modified existing drugs to increase their binding to CD36, which significantly improved both their water solubility and ability to enter cells – two properties that typically work against each other in traditional drug design.
“This breakthrough discovery will force us to rethink how we approach efficacy and pharmacokinetics and toxicity,” Li said. “We believe it will also eventually change how regulatory agencies like the FDA evaluate and approve new endocytic drugs.”
This discovery could impact far more than just cancer drugs. CD36 is found in many parts of the body — including the gut, brain, and skin — opening up new possibilities:
- Pills instead of IVs for many treatments
- Drugs that cross the blood-brain barrier, a challenge in treating brain diseases
- Creams or patches that work better through the skin
“In the next 10 to 20 years, this may become a foundational approach in drug discovery and a new research field within medicinal chemistry,” Li said. “We feel incredibly lucky to have made this discovery and opened the door to hope for previously untreatable diseases.”
Paper Summary
Methodology
Researchers used multiple complementary approaches to investigate CD36’s role in cellular drug uptake. They created biotin-labeled probe compounds that mimic PROTACs, which were used to identify membrane proteins involved in PROTAC uptake. Through pull-down assays coupled with mass spectrometry, they identified CD36 as a key membrane protein binding to PROTACs. To confirm CD36’s functional role, the team used genetic knockdown techniques (shRNA) to reduce CD36 levels in cancer cell lines including LNCaP prostate cancer cells and HCC1806 breast cancer cells. They then measured cellular uptake of various drugs using metabolomic analyses via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Additionally, they designed fluorescently-labeled versions of several drugs to visualize uptake using confocal microscopy. To demonstrate practical applications, they created structurally modified versions of existing drugs designed to better interact with CD36 and tested their efficacy in both cell cultures and mouse tumor models.
Results
The study revealed that CD36 is essential for cellular uptake of numerous drugs with molecular weights ranging from 543 to 2,245 Da, including PROTACs (SIM1-Me, MZ1, ARV-110), as well as other large or polar drugs such as rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin. Cells with reduced CD36 showed dramatically decreased uptake of these compounds—for example, accumulation of the PROTAC molecules SIM1-Me and ARV-110 decreased 5.6 and 19.6-fold, respectively, in cells with CD36 knockdown. Visually, fluorescent drug analogs failed to enter cells lacking CD36. The research team successfully created modified versions of drugs that more effectively engage CD36, significantly enhancing their cellular uptake and potency. For example, a modified version of MZ1 (called MZ1-C14-Na) showed 16.2-fold greater cancer cell-killing potency than the parent compound. In mouse tumor models, these modified drugs demonstrated superior anti-tumor effects without increased toxicity.
Limitations
The study primarily focused on prostate and breast cancer cell lines, so the findings may not apply equally to all cell types. While CD36 was identified as a major pathway for drug uptake, the researchers acknowledge that some residual drug uptake occurred even after CD36 depletion, suggesting alternative uptake mechanisms might exist. Additionally, the study notes that CD36 expression varies among patients and tissues, which could affect how well this approach works in different individuals. The modified drugs were tested in mouse models but have not yet been evaluated in human clinical trials. The researchers also mention that variations in CD36, particularly its glycosylation (sugar modifications), might impact how it functions in drug uptake across different tissues.
Funding and Disclosures
The research was supported by the University of Texas Health San Antonio, startup funds and Arkansas Research Alliance Endowed Chair Fund at the University of Arkansas for Medical Sciences to Hong-Yu Li, and Fred and Janet Sanfilippo Distinguished Professor funds and Duke University School of Medicine start-up funds to Hui-Kuan Lin. The researchers also received support from the National Institutes of Health (R01 CA277682) and the Arkansas Bioscience Institute. Two of the authors (Hong-Yu Li and Zhengyu Wang) have filed a patent application related to the findings, and Hong-Yu Li is a shareholder of Univiatis, LLC and Sirronatx, Inc., indicating potential commercial interests in the application of this research.
Publication Information
The paper titled “CD36-mediated endocytosis of proteolysis-targeting chimeras” was published in Cell (Volume 188, pages 1-19) on June 12, 2025, and was authored by Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, and colleagues from the University of Texas Health Science Center at San Antonio, University of Arkansas for Medical Sciences, Duke University Medical Center, and Wake Forest University School of Medicine. The paper is available online at https://doi.org/10.1016/j.cell.2025.03.036.
